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The ISME Journal Jan 2024Hadarchaeota inhabit subsurface and hydrothermally heated environments, but previous to this study, they had not been cultured. Based on metagenome-assembled genomes,...
Hadarchaeota inhabit subsurface and hydrothermally heated environments, but previous to this study, they had not been cultured. Based on metagenome-assembled genomes, most Hadarchaeota are heterotrophs that grow on sugars and amino acids, or oxidize carbon monoxide or reduce nitrite to ammonium. A few other metagenome-assembled genomes encode alkyl-coenzyme M reductases (Acrs), β-oxidation, and Wood-Ljungdahl pathways, pointing toward multicarbon alkane metabolism. To identify the organisms involved in thermophilic oil degradation, we established anaerobic sulfate-reducing hexadecane-degrading cultures from hydrothermally heated sediments of the Guaymas Basin. Cultures at 70°C were enriched in one Hadarchaeon that we propose as Candidatus Cerberiarchaeum oleivorans. Genomic and chemical analyses indicate that Ca. C. oleivorans uses an Acr to activate hexadecane to hexadecyl-coenzyme M. A β-oxidation pathway and a tetrahydromethanopterin methyl branch Wood-Ljungdahl (mWL) pathway allow the complete oxidation of hexadecane to CO2. Our results suggest a syntrophic lifestyle with sulfate reducers, as Ca. C. oleivorans lacks a sulfate respiration pathway. Comparative genomics show that Acr, mWL, and β-oxidation are restricted to one family of Hadarchaeota, which we propose as Ca. Cerberiarchaeaceae. Phylogenetic analyses further indicate that the mWL pathway is basal to all Hadarchaeota. By contrast, the carbon monoxide dehydrogenase/acetyl-coenzyme A synthase complex in Ca. Cerberiarchaeaceae was horizontally acquired from Bathyarchaeia. The Acr and β-oxidation genes of Ca. Cerberiarchaeaceae are highly similar to those of other alkane-oxidizing archaea such as Ca. Methanoliparia and Ca. Helarchaeales. Our results support the use of Acrs in the degradation of petroleum alkanes and suggest a role of Hadarchaeota in oil-rich environments.
Topics: Anaerobiosis; Phylogeny; Mesna; Alkanes; Oxidation-Reduction; Oxidoreductases; Sulfates
PubMed: 38365230
DOI: 10.1093/ismejo/wrad004 -
ACS Omega Feb 2024This study aimed at designing an S-protected thiolated β-cyclodextrin (β-CD) exhibiting enhanced mucoadhesive properties. The native β-CD was thiolated with...
This study aimed at designing an S-protected thiolated β-cyclodextrin (β-CD) exhibiting enhanced mucoadhesive properties. The native β-CD was thiolated with phosphorus pentasulfide resulting in a thiolated β-CD (β-CD-SH) and subsequently S-protected with 2-mercaptoethanesulfonate (MESNA) to form β-CD-SS-MESNA. The structure of the novel excipient was confirmed by H NMR and Fourier-transform infrared spectroscopy. The sulfhydryl content of β-CD-SH, determined by Ellman's test, was 2281.00 ± 147 μmol/g, and it was decreased to 45.93 ± 19.40 μmol/g by S-protection. Due to thiolation and S-protection, the viscosity of the mixture of mucus with β-CD-SH and β-CD-SS-MESNA increased 1.8 and 4.1-fold, compared to native β-CD, respectively. The unprotected β-CD-SH diffused to a lesser extent into the mucus than native β-CD, while S-protected β-CD-SS-MESNA showed the highest mucodiffusion among the applied CDs. A 1.5- and 3.0-fold higher cellular uptake of β-CD-SH and β-CD-SS-MESNA, compared to the native one, was established on Caco-2 cell line by flow cytometry, respectively, causing slightly decreased cell viability. On account of the enhanced mucoadhesion, this higher cellular uptake does not affect the application potential of β-CD-SS-MESNA as an oral drug delivery system since the carrier remains in the mucus and does not reach the underlying epithelial layer. According to these results, the S-protection of β-CD-SH with MESNA promotes improved mucodiffusion, strong mucoadhesion, and prolonged mucosal residence time.
PubMed: 38343993
DOI: 10.1021/acsomega.3c08836 -
Otolaryngologia Polska = the Polish... Feb 2024<b><br>Introduction:</b> 'Off-label drug use' refers to the administration of drugs for unapproved indications or age groups, a different dosage or...
<b><br>Introduction:</b> 'Off-label drug use' refers to the administration of drugs for unapproved indications or age groups, a different dosage or other form of administration. Considering the legal issues, there clearly exists a need to implement rules that would regulate the use of pharmaceuticals outside the scope of a marketing authorisation. The brevity and diversity of Polish laws in the field of health care leads to many interpretative doubts associated with particular legal acts.</br> <b><br>Aim:</b> We aimed to present clinical examples from everyday practice of off-label drug use from the medical and legal perspectives, and to support it with relevant legal acts.</br> <b><br>Material and method:</b> Off-label drug use in various otolaryngology subspecialties - otology (mesna), laryngology (bevacizumab, cidofovir and botulinum toxin) and head and neck surgery (botulinum toxin) - are presented and discussed in detail.</br> <b><br>Results:</b> Fourteen Polish legal acts regarding off-label drug use and 4 from EU legislation are commented on. The algorithm of cascade of decision-making processes in off-label drug use is shown.</br> <b><br>Conclusions:</b> Off-label use of medicinal products is not prohibited in Poland or the EU; nevertheless, it is undeniable that the unclear legal situation regarding the use of medicinal products for nonregistered indications creates difficulties. To minimise a doctor's liability risk, obtaining the informed consent from the patient for such treatment is advisable.</br>.
Topics: Humans; Off-Label Use; Poland; Bevacizumab; Botulinum Toxins; Otolaryngology
PubMed: 38332710
DOI: 10.5604/01.3001.0054.1185 -
Frontiers in Veterinary Science 2023Feline idiopathic cystitis is a common, chronic-relapsing disorder of the lower urinary tract. In addition to environmental modification/enrichment, long-term and safe...
Uroprotective and pain-relieving effect of dietary supplementation with micronized palmitoyl-glucosamine and hesperidin in a chronic model of cyclophosphamide-induced cystitis.
INTRODUCTION
Feline idiopathic cystitis is a common, chronic-relapsing disorder of the lower urinary tract. In addition to environmental modification/enrichment, long-term and safe treatment targeting specific pathophysiological changes may be of help. In this context, effective dietary interventions hold clinical promise. Palmitoyl-glucosamine (PGA) and hesperidin (HSP) are safe and authorized feed ingredients for animal nutrition under European regulations.
METHODS
The current study aimed to investigate whether a 3:1 mixture of micronized PGA and HSP could represent a novel mechanism-oriented approach to chronic cystitis management. A newly validated rat model of cyclophosphamide (CYP)-induced chronic cystitis was used (40 mg/kg, three intraperitoneal injections every 3rd day). Animals were randomized to orally receive either vehicle or PGA-HSP at a low (72 + 24 mg/kg) or high (doubled) dose for 13 days, starting 3 days before the chronic CYP protocol, with mesna (2-mercaptoethane-sulfonate) being used as a reference drug.
RESULTS
Higher PGA-HSP dose was effective at relieving chronic visceral pain, as measured by mechanical allodynia test (von Frey test). The severity of cystitis was also significantly improved, as shown by the reduced sonographic thickening of the bladder wall, as well as the decrease in edema, bleeding and bladder to body weight ratio compared to the vehicle treated group. A significant decrease of MPO activity, MDA level and fibrosis at Masson's trichrome staining was also observed in animals administered PGA-HSP in comparison to vehicle treated ones. The CYP-induced increase in bladder mRNA expression of pro-inflammatory cytokines was also significantly counteracted by the study mixture. Moreover, CYP-induced bladder mast cell accumulation and releasability were significantly decreased by PGA-HSP (even at the low dose), as determined by metachromatic staining, chymase and tryptase immunostaining as well as enzyme-linked immunosorbent assay for histamine and 5-hydoxytriptamine.
DISCUSSION
PGA-HSP is able to block CYP-induced decrease of tight junction proteins, claudin-1 and occludin, thus preserving the urothelial bladder function. Finally, neuroinflammatory changes were investigated, showing that dietary supplementation with PGA-HSP prevented the activation of neurons and non-neuronal cells (i.e., microglia, astrocytes and mast cells) at the spinal level, and counteracted CYP-induced increase of spinal mRNA encoding for pro-inflammatory cytokines. Altogether, the present findings confirm the uroprotective and pain-relieving effect of PGA-HSP and pave the way to potential and relevant clinical applications of the study supplement in feline idiopathic cystitis.
PubMed: 38249555
DOI: 10.3389/fvets.2023.1327102 -
Journal of Osteopathic Medicine Mar 2024An important diagnostic tool, ultrasound (US) has been incorporated into the curriculum of medical schools for more than 20 years. In the last decade, the interest in...
CONTEXT
An important diagnostic tool, ultrasound (US) has been incorporated into the curriculum of medical schools for more than 20 years. In the last decade, the interest in US educational research has experienced exponential growth but mostly from Medical Doctor (MD)-granted schools. The extent to which US is embedded in the curricula of the colleges of osteopathic medicine (COM) still requires a comprehensive evaluation.
OBJECTIVES
This survey is designed to evaluate the current status of US teaching in COMs with an emphasis on the inclusion of the US in osteopathic manipulative medicine (OMM) training.
METHODS
An anonymous, voluntary, 22-question online survey was created and administered to all COMs to collect data about the current state of US teaching. A descriptive analysis was performed to describe and summarize the final data. Fisher's exact test was utilized for the comparison of study variables.
RESULTS
We received responses from 36 of the 43 (83.7 %) COMs invited to participate in the survey, all of which had US training within their curriculum, most commonly integrated into the year 1 curriculum (86.1 %). Focused US training is incorporated into 83.3 % of these schools (30 of 36). Focused US training is covered in 83.3 % of schools (30 of 36). US is mostly taught in the anatomy course (38.8 %). US is incorporated in the OMM course in 12 of 36 schools (33.3 %). The majority of respondents feel that US training will make osteopathic students more competitive in the job market (88.9 %) and want more US in their curriculum (86.1 %). The idea that US is useful for a better understanding of the key OMM concepts is believed by 62.9 % of respondents. The major obstacle to the implementation of US in the curriculum is having appropriately trained faculty (86.1 %). The majority of the respondents did not feel that an adequate budget is a handicap to implementing US in the curriculum.
CONCLUSIONS
US is included within the curriculum of all respondents to our survey, a third of whom included US within their OMM curriculum. US is treated as a useful and important skill for future osteopathic physicians. The majority of COMs desire more US training in the curriculum. The main barrier to implementing US in the curriculum is the lack of appropriately trained faculty.
Topics: Humans; Schools, Medical; Curriculum; Emotions; Manipulation, Osteopathic; Mesna
PubMed: 38053432
DOI: 10.1515/jom-2023-0027 -
JCEM Case Reports Sep 2023Primary pituitary T-lymphoblastic lymphoma is a rare clinical entity. A 45-year-old woman presented with headache, left-eye blurry vision, diplopia, ophthalmoplegia, and...
Primary pituitary T-lymphoblastic lymphoma is a rare clinical entity. A 45-year-old woman presented with headache, left-eye blurry vision, diplopia, ophthalmoplegia, and ptosis. Magnetic resonance imaging of the brain showed a sellar mass most likely consistent with a pituitary macroadenoma. Laboratory evaluation disclosed secondary hypothyroidism, secondary adrenal insufficiency, and hyperprolactinemia. The mass was removed by transsphenoidal resection, and subsequent immunophenotyping revealed T-cell lymphoblastic lymphoma. Secondary workup confirmed lymphomatous confinement to the central nervous system. Following resection, the patient's headaches improved, but she experienced persistent visual deficits and palsies of cranial nerves III, IV, and VI. The chemotherapy regimen consisted of high-dose methotrexate, followed by alternating cycles of cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride (Adriamycin), dexamethasone (cyclophosphamide, mesna, vincristine sulfate, doxorubicin hydrochloride, dexamethasone), and methotrexate/cytarabine. Since receiving chemotherapy, there has been an improvement in numbness, ptosis, left orbital pressure, and headaches. This case represents only the eighth example of T-cell primary pituitary lymphoma, and the youngest patient to receive the diagnosis.
PubMed: 37908217
DOI: 10.1210/jcemcr/luad097 -
Cancers Oct 2023Doxorubicin is a widely used anticancer agent as a first-line treatment for various tumor types, including sarcomas. Its use is hampered by adverse events, among which...
Prospective, Multicenter Phase II Trial of Non-Pegylated Liposomal Doxorubicin Combined with Ifosfamide in First-Line Treatment of Advanced/Metastatic Soft Tissue Sarcomas.
Doxorubicin is a widely used anticancer agent as a first-line treatment for various tumor types, including sarcomas. Its use is hampered by adverse events, among which is the risk of dose dependence. The potential cardiotoxicity, which increases with higher doses, poses a significant challenge to its safe and effective application. To try to overcome these undesired effects, encapsulation of doxorubicin in liposomes has been proposed. Caelyx and Myocet are different formulations of pegylated (PLD) and non-pegylated liposomal doxorubicin (NPLD), respectively. Both PLD and NPLD have shown similar activity compared with free drugs but with reduced cardiotoxicity. While the hand-foot syndrome exhibits a high occurrence among patients treated with PLD, its frequency is notably reduced in those receiving NPLD. In this prospective, multicenter, one-stage, single-arm phase II trial, we assessed the combination of NPLD and ifosfamide as first-line treatment for advanced/metastatic soft tissue sarcoma (STS). Patients received six cycles of NPLD (50 mg/m) on day 1 along with ifosfamide (3000 mg/m on days 1, 2, and 3 with equidose MESNA) administered every 3 weeks. The overall response rate, yielding 40% (95% CI: 0.29-0.51), resulted in statistical significance; the disease control rate stood at 81% (95% CI: 0.73-0.90), while only 16% (95% CI: 0.08-0.24) of patients experienced a progressive disease. These findings indicate that the combination of NPLD and ifosfamide yields a statistically significant response rate in advanced/metastatic STS with limited toxicity.
PubMed: 37894403
DOI: 10.3390/cancers15205036 -
Analytical Methods : Advancing Methods... Nov 2023Modafinil (MOD) is a CNS stimulant used for the treatment of narcolepsy, shift work sleep disorder, excessive daytime sleepiness, and post-COVID 19 neurological...
Modafinil (MOD) is a CNS stimulant used for the treatment of narcolepsy, shift work sleep disorder, excessive daytime sleepiness, and post-COVID 19 neurological symptoms. In the literature, there is no report of square wave voltammetric (SWV) methods being used for the determination of MOD. This study describes, for the first time, the construction and evaluation of the analytical performance of a novel sensor for ultrasensitive SWV detection of MOD. The sensor was constructed by integration of silver nanoparticles (Ag) on Mesna (MSN) layers over a pencil graphite electrode (PGE) surface. The interface and morphological characteristics of the fabricated Ag@MSN/PGE sensor were investigated cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and scanning electron microscopy (SEM). This sensor was found to enhance the electro-oxidation of MOD. The combination of Ag@MSN/PGE with SWV enabled the determination of MOD in its bulk form and in pharmaceutical and biological matrices at the nanomolar scale (LOD = 28.59 nM) with excellent recoveries. This study represents the first report describing an electrochemical procedure for MOD detection in human plasma. The established SWV method was also validated, and the results were consistent with ICH criteria. Finally, the presented SWV procedure provides a facile, sensitive, rapid, and cost-effective approach compared to other existing methods.
Topics: Humans; Metal Nanoparticles; Modafinil; Mesna; Silver; Electrochemical Techniques; Graphite
PubMed: 37847517
DOI: 10.1039/d3ay01401k -
Chembiochem : a European Journal of... Jan 2024Methanogenic and methanotrophic archaea play important roles in the global carbon cycle by interconverting CO and methane. To conserve energy from these metabolic...
Thiol-Disulfide Exchange Kinetics and Redox Potential of the Coenzyme M and Coenzyme B Heterodisulfide, an Electron Acceptor Coupled to Energy Conservation in Methanogenic Archaea.
Methanogenic and methanotrophic archaea play important roles in the global carbon cycle by interconverting CO and methane. To conserve energy from these metabolic pathways that happen close to the thermodynamic equilibrium, specific electron carriers have evolved to balance the redox potentials between key steps. Reduced ferredoxins required to activate CO are provided by energetical coupling to the reduction of the high-potential heterodisulfide (HDS) of coenzyme M (2-mercaptoethanesulfonate) and coenzyme B (7-mercaptoheptanoylthreonine phosphate). While the standard redox potential of this important HDS has been determined previously to be -143 mV (Tietze et al. 2003 DOI: 10.1002/cbic.200390053), we have measured thiol disulfide exchange kinetics and reassessed this value by equilibrating thiol-disulfide mixtures of coenzyme M, coenzyme B, and mercaptoethanol. We determined the redox potential of the HDS of coenzyme M and coenzyme B to be -16.4±1.7 mV relative to the reference thiol mercaptoethanol (E '=-264 mV). The resulting E ' values are -281 mV for the HDS, -271 mV for the homodisulfide of coenzyme M, and -270 mV for the homodisulfide of coenzyme B. We discuss the importance of these updated values for the physiology of methanogenic and methanotrophic archaea and their implications in terms of energy conservation.
Topics: Mesna; Archaea; Sulfhydryl Compounds; Mercaptoethanol; Disulfides; Carbon Dioxide; Electrons; Electron Transport; Methane; Oxidation-Reduction
PubMed: 37815851
DOI: 10.1002/cbic.202300595 -
Otolaryngologia Polska = the Polish... Jul 2023<b>Introduction:</b> Surgery is still the method of choice in chronic otitis media with cholesteatoma. Except for some specific clinical situations, classic...
<b>Introduction:</b> Surgery is still the method of choice in chronic otitis media with cholesteatoma. Except for some specific clinical situations, classic canal wall up technique (CWU), remains a gold standard as a primary treatment in most departments. Unfortunately, the risk of recurrence in such an approach is estimated at 9 to even 70%. This fact prompts researchers to look for ways to reduce those unfavourable statistics. One of the recognized methods supporting the removal of cholesteatoma is the intraoperative use of mesna (sodium 2-mercaptoethanesulfonate). This synthetic sulphur compound disrupts disulfide bridges in polypeptide chains, thanks to which it facilitates matrix preparation.</br></br> <b>Aim:</b> To evaluate the effect of intraoperative use of mesna on the treatment outcomes in patients with chronic otitis media with cholesteatoma operated on by means of the canal wall up technique (CWU).</br></br> <b>Material and methods:</b> 459 surgical reports of patients with middle ear cholesteatoma were analyzed. In total, 52 adult patients with no history of previous ear surgery operated on by means of the CWU technique by the same experienced otosurgeon with all follow-up data available were included in the study. Twenty-six were operated on with the use of mesna (mesna group) and 26 by means of the classic CWU technique (control / no-mesna group). There were 28 women and 24 men with a mean age of 41 years.</br></br> <b>Main Outcome Measure(s):</b> Postoperative hearing results and cholesteatoma recidivism rate.</br></br> <b>Results:</b> Overall recidivism rate was 21.15 %. It was higher in the no-mesna (26.9%) than in the mesna group (15.4%) - although the outcomes were better in the mesna group, the difference was not statistically significant (P = 0.49715). Hearing gain was better in the mesna than in the no-mesna group (10 dB vs 7 dB), but the difference was not statistically significant (P = 0.20089).</br></br> <b>Conclusions:</b> Our preliminary results show that mesna reduces recidivism rates in patients with cholesteatoma. Further study with the analysis of a larger group of patients is needed to prove it statistically.
PubMed: 37772375
DOI: 10.5604/01.3001.0016.3415