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Amino Acids Jul 2024Carnosine's protective effect in rodent models of glycoxidative stress have provided a rational for translation of these findings in therapeutic concepts in patient with...
Carnosine's protective effect in rodent models of glycoxidative stress have provided a rational for translation of these findings in therapeutic concepts in patient with diabetic kidney disease. In contrast to rodents however, carnosine is rapidly degraded by the carnosinase-1 enzyme. To overcome this hurdle, we sought to protect hydrolysis of carnosine by conjugation to Methoxypolyethylene glycol amine (mPEG-NH). PEGylated carnosine (PEG-car) was used to study the hydrolysis of carnosine by human serum as well as to compare the pharmacokinetics of PEG-car and L-carnosine in mice after intravenous (IV) injection. While L-carnosine was rapidly hydrolyzed in human serum, PEG-car was highly resistant to hydrolysis. Addition of unconjugated PEG to carnosine or PEG-car did not influence hydrolysis of carnosine in serum. In mice PEG-car and L-carnosine exhibited similar pharmacokinetics in serum but differed in half-life time (t) in kidney, with PEG-car showing a significantly higher t compared to L-carnosine. Hence, PEGylation of carnosine is an effective approach to prevent carnosine degradations and to achieve higher renal carnosine levels. However, further studies are warranted to test if the protective properties of carnosine are preserved after PEGylation.
Topics: Carnosine; Animals; Polyethylene Glycols; Hydrolysis; Dipeptidases; Mice; Humans; Kidney; Male
PubMed: 38960916
DOI: 10.1007/s00726-024-03405-6 -
European Journal of Pediatrics Jul 2024Duchenne muscular dystrophy is life-limiting. Cardiomyopathy, which mostly ensues in the second decade of life, is the main cause of death. Treatment options are still...
UNLABELLED
Duchenne muscular dystrophy is life-limiting. Cardiomyopathy, which mostly ensues in the second decade of life, is the main cause of death. Treatment options are still limited. The TAMDMD (NCT03354039) trial assessed motor function, muscle strength and structure, laboratory biomarkers, and safety in 79 ambulant boys with genetically confirmed Duchenne muscular dystrophy, 6.5-12 years of age, receiving either daily tamoxifen 20 mg or placebo for 48 weeks. In this post-hoc analysis, available echocardiographic data of ambulant patients recruited at one study centre were retrieved and compared before and after treatment. Data from 14 patients, median 11 (interquartile range, IQR, 11-12) years of age was available. Baseline demographic characteristics were similar in participants assigned to placebo (n = 7) or tamoxifen (n = 7). Left ventricular end-diastolic diameter in the placebo group (median and IQR) was 39 (38-41) mm at baseline and 43 (38-44) mm at study end, while it was 44 (41-46) mm at baseline and 41 (37-46) mm after treatment in the tamoxifen group. Left ventricular fractional shortening in the placebo group was 35% (32-38%) before and 33% (32-36%) after treatment, while in the tamoxifen group it was 34% (33-34%) at baseline and 35% (33-35%) at study end. No safety signals were detected.
CONCLUSION
This hypothesis-generating post-hoc analysis suggests that tamoxifen over 48 weeks is well tolerated and may help preserving cardiac structure and function in Duchenne muscular dystrophy. Further studies are justified.
CLINICALTRIALS
gov Identifier: EudraCT 2017-004554-42, NCT03354039 What is known: • Duchenne muscular dystrophy (DMD) is life-limiting. Cardiomyopathy ensues in the second decade of life and is the main cause of death. Treatment options are still limited. • Tamoxifen reduced cardiac fibrosis in mice and improved cardiomyocyte function in human-induced pluripotent stem cell-derived cardiomyocytes.
WHAT IS NEW
• In this post-hoc analysis of the TAMDMD trial among 14 boys, median 11 years of age, treated with either tamoxifen or placebo for 48 weeks, treatment was well-tolerated. • A visual trend of improved left-ventricular dimensions and better systolic function preservation generates the hypothesis of a potential beneficial effect of tamoxifen in DMD cardiomyopathy.
PubMed: 38960907
DOI: 10.1007/s00431-024-05670-9 -
Human Reproduction (Oxford, England) Jul 2024Does vitrification cryopreservation of embryos for more than 5 years affect the pregnancy outcomes after frozen embryo transfer (FET)?
STUDY QUESTION
Does vitrification cryopreservation of embryos for more than 5 years affect the pregnancy outcomes after frozen embryo transfer (FET)?
SUMMARY ANSWER
Vitrification cryopreservation of good-quality blastocysts for more than 5 years is associated with a decrease in the implantation rate (IR) and live birth rate (LBR).
WHAT IS KNOWN ALREADY
Previous studies have predominantly focused on embryos cryopreserved for relatively short durations (less than 5 years), yet the impact of extended cryopreservation duration on pregnancy outcomes remains a controversial issue. There is a relative scarcity of data regarding the efficacy and safety of storing embryos for 5 years or longer.
STUDY DESIGN, SIZE, DURATION
This retrospective study involved 36 665 eligible vitrified-thawed embryo transfer cycles from 1 January 2016 to 31 December 2022, at a single fertility center in China.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Patients were divided into three groups according to embryo storage time: Group 1 consisted of 31 565 cycles, with storage time of 0-2 years; Group 2 consisted of 4458 cycles, with a storage time of 2-5 years; and Group 3 included 642 cycles, with storage time exceeding 5 years. The main outcome measures were IR and LBR. Secondary outcome variables included rates of biochemical pregnancy, multiple pregnancy, ectopic pregnancy, and miscarriage, as well as neonatal outcomes. Reproductive outcomes were analyzed as binary variables. Multivariate logistic regression analysis was used to explore the effect of preservation time on pregnancy outcomes after correcting for confounding factors. In addition, we also assessed neonatal outcomes, such as large for gestational age (LGA) and small for gestational age (SGA).
MAIN RESULTS AND THE ROLE OF CHANCE
IRs in the three groups (0-2, 2-5, and >5 years) were 37.37%, 39.03%, and 35.78%, respectively (P = 0.017), and LBRs in the three groups were 37.29%, 39.09%, and 34.91%, respectively (P = 0.028). After adjustment for potential confounding factors, compared with the 0-2 years storage group, prolonged embryo vitrification preservation time (2-5 years or >5 years) did not affect secondary outcomes such as rates of biochemical pregnancy, multiple pregnancy, ectopic pregnancy, and miscarriage (P > 0.05). But cryopreservation of embryos for more than 5 years reduced the IR (adjusted odds ratio (aOR) 0.82, 95% CI 0.69-0.97, P = 0.020) and LBR (aOR 0.76, 95% CI 0.64-0.91, P = 0.002). Multivariate stratified analysis also showed that prolonging the cryopreservation time of blastocysts (>5 years) reduced the IR (aOR 0.78, 95% CI 0.62-0.98, P = 0.033) and LBR (aOR 0.68, 95% CI 0.53-0.87, P = 0.002). However, no effect on cleavage embryos was observed (P > 0.05). We further conducted stratified analyses based on the number and quality of frozen blastocysts transferred, and the results showed that the FET results after transfers of good-quality blastocysts in the >5 years storage group were negatively affected. However, the storage time of non-good-quality blastocysts was not significantly associated with pregnancy outcomes. Regarding the neonatal outcomes (of singletons), embryo vitrification preservation time had no effect on preterm birth rates, fetal birth weight, or neonatal sex ratios. However, as the storage time increased, rates of SGA (5.60%, 4.10%, and 1.18%) decreased, while rates of LGA (5.22%, 6.75%, and 9.47%) increased (P < 0.05). After adjusting for confounding factors, the increase in LGA and the decrease in SGA were significantly correlated with the duration of storage time.
LIMITATIONS, REASONS FOR CAUTION
This was a retrospective study using data from a single fertility center, even though the data had been adjusted, our findings still need to be validated in further studies.
WIDER IMPLICATIONS OF THE FINDINGS
With the full implementation of the two-child policy in China, there may be more patients whose embryos have been frozen for a longer time in the future. Patients should be aware that the IR and LBR of blastocysts are negatively affected when the cryopreservation time is longer than 5 years. Couples may therefore consider shortening the time until FET treatment.
STUDY FUNDING/COMPETING INTEREST(S)
This study was supported by the National Nature Science Foundation of China (No. 82101672), Science and Technology Projects in Guangzhou (No. 2024A03J0180), General Guidance Program for Western Medicine of Guangzhou Municipal Health Commission (No. 20231A011096), and the Medical Key Discipline of Guangzhou (2021-2023). None of the authors have any conflicts of interest to declare.
TRIAL REGISTRATION NUMBER
N/A.
PubMed: 38960877
DOI: 10.1093/humrep/deae150 -
HPB : the Official Journal of the... Jun 2024Three-dimensional reconstruction of the liver offers several advantages to the surgeon before and during liver resection. This review discusses the factors behind the... (Review)
Review
BACKGROUND
Three-dimensional reconstruction of the liver offers several advantages to the surgeon before and during liver resection. This review discusses the factors behind the use of liver 3-D reconstruction.
METHODS
Systematic electronic search, according to PRISMA criteria, was performed. A literature search of scientific papers was performed until October 2023. Articles were chosen based on reference to 3-D liver reconstruction and their use in liver surgery. GRADE methodology and the modified Newcastle-Ottawa scale were used to assess the quality of the studies.
RESULTS
The research included 47 articles and 7724 patients were analyzed. Preoperative planning was performed with 3-D liver reconstruction in the 87.2% of the studies. Most of preoperative 3-D liver reconstructions were performed in the planning of complex or major hepatectomies. Complex hepatectomies were performed in 64.3% patients. The 55.3% of the studies reported an improved navigation and accuracy during liver resection. Four studies (8.6%) on living donor liver transplant (LDLT) concluded that 3-D liver reconstruction is useful for graft selection and vascular preservation. Nine papers (19.1%) reported an accurate measurement of future liver remnant.
CONCLUSION
Liver 3-D reconstruction helps surgeons in the planning of liver surgery, especially in liver graft and complex liver resections, increasing the accuracy of the surgical resection.
PubMed: 38960762
DOI: 10.1016/j.hpb.2024.06.006 -
International Journal of Spine Surgery Jul 2024Anterior cervical discectomy and fusion (ACDF) for the surgical treatment of cervical degenerative disease often includes an intervertebral cage, which restores disc...
BACKGROUND
Anterior cervical discectomy and fusion (ACDF) for the surgical treatment of cervical degenerative disease often includes an intervertebral cage, which restores disc height and lordosis while promoting fusion . Cage materials include titanium (TTN) or polyetheretherketone (PEEK). Controversy in material selection stems from higher fusion rates with TNN, despite a higher subsidence rate, while PEEK cages demonstrate superior preservation of interspace height. Combining the advantages of both materials, TTN-coated PEEK (TCPEEK) cages were developed, featuring a PEEK core with similar stiffness to the bone, enveloped with a TTN coat, improving osteointegration. However, the potential superiority of TCPEEK over TTN cages has not been investigated. This study aimed to compare clinical and radiographic outcomes following single- or double-level ACDF using either TTN or TCPEEK cages.
METHODS
This retrospective single-center study included patients undergoing single- or double-level ACDF between 2017 and 2019. Clinical outcomes included the Neck Disability Index and revision surgery incidence. Radiographic parameters included cervical and segmental lordosis, C2 to C7 sagittal vertical axis, fusion, subsidence, and adjacent segment degeneration at a minimum 12-month follow-up.
RESULTS
A total of 45 patients (16 TTN; 29 TCPEEK) and 58 cervical levels (21 TTN; 37 TCPEEK) were included. Both cages significantly improved Neck Disability Index scores (TTN -10.0; TCPEEK -14.1) without significant differences. Two single-level TCPEEK patients required revision surgery due to non-union. In the radiological assessments, no significant difference was found for subsidence rates (TTN 52.4%; TCPEEK 56.8%), adjacent segment degeneration, cervical and segmental lordosis, and changes in C2 to C7 sagittal vertical axis. Though not statistically significant, fusion rates trended slightly higher with TTN (90.5%) vs TCPEEK cages (86.5%).
CONCLUSION
TTN and TCPEEK cages achieve satisfactory clinical and radiological outcomes in single- or double-level ACDF. This finding suggests that the choice between them can be based on other factors, such as surgeon preference or availability, rather than specific material properties.
CLINICAL RELEVANCE
This study found that the selection of ACDF cage material did not affect clinical outcomes.
PubMed: 38960609
DOI: 10.14444/8610 -
Clinics in Geriatric Medicine Aug 2024Pressure injuries are a common chronic wound in the older adult. Care of pressure injuries is an interprofessional effort and involves physicians, nurses, registered... (Review)
Review
Pressure injuries are a common chronic wound in the older adult. Care of pressure injuries is an interprofessional effort and involves physicians, nurses, registered dieticians, rehabilitation therapists, and surgical subspecialties. Numerous treatment modalities exist but have varying evidence to substantiate their efficacy. All primary and other care providers, particularly geriatricians, need to be aware of current evidence-based prevention and treatment standards. When healing is not expected, palliative care should be considered to avoid futile procedures and preserve dignity and quality of life.
Topics: Humans; Pressure Ulcer; Aged; Wound Healing; Palliative Care
PubMed: 38960532
DOI: 10.1016/j.cger.2023.12.006 -
Arthroscopy : the Journal of... Jul 2024The 3 primary factors involved with preservation of the hip joint are femoroacetabular impingement (FAI), hip dysplasia, and femoral torsion abnormalities. Each of these... (Review)
Review
The 3 primary factors involved with preservation of the hip joint are femoroacetabular impingement (FAI), hip dysplasia, and femoral torsion abnormalities. Each of these factors affects the health of the acetabular labrum and femoroacetabular cartilage. The appropriate surgical treatments for each of these factors include arthroscopic or open femoroplasty or acetabuloplasty for FAI, periacetabular osteotomy (PAO) for acetabular dysplasia, and de-rotational femoral osteotomy for femoral torsion abnormalities. When evaluating patients with prearthritic hip conditions, orthopaedic surgeons should be aware of the various factors involved in hip joint preservation and, if surgery is indicated, surgeons should be sure to address all factors that need surgical treatment rather than focusing on the most obvious issue or injury (e.g., a labral tear). The purpose of this infographic is to illustrate the importance of the factors involved in hip joint preservation and the appropriate treatments for pathology in any of these factors.
Topics: Humans; Femoracetabular Impingement; Hip Joint; Hip Dislocation; Arthroscopy; Osteotomy; Acetabulum; Femur
PubMed: 38960506
DOI: 10.1016/j.arthro.2024.04.002 -
BMJ Open Jul 2024This study compares rectal administration with vaginal administration of progesterone as luteal phase support in hormone replacement therapy frozen embryo transfer...
Rectal versus vaginal progesterone administration for luteal phase support in the hormone replacement therapy frozen embryo transfer (HRT-FET) cycle: protocol for a non-inferiority randomised controlled trial.
INTRODUCTION
This study compares rectal administration with vaginal administration of progesterone as luteal phase support in hormone replacement therapy frozen embryo transfer (HRT-FET) cycles. The reason for comparing the two routes of administration is that rectal administration has been suggested to be more patient friendly.
METHODS AND ANALYSIS
This study is a randomised controlled trial comparing the ongoing pregnancy rate (OPR) at week 12 in HRT-FET cycles after rectal administered progesterone as the only administered progesterone compared with a vaginal luteal phase support regimen. All patients are enrolled from a Danish public fertility clinic and randomised to one of two groups, with 305 patients receiving embryo transfer assigned to each group. Endometrial preparation includes 6 mg oestradiol daily. The intervention group receives rectally administered progesterone (400 mg/12 hours) and the control group receives vaginally administered progesterone (400 mg/12 hours). If P4 is <35 nmol/L on blastocyst transfer day an additional rectal luteal phase rescue regimen is started (control group). Thawing and transferring of a single autologous vitrified blastocyst is scheduled on the sixth day of progesterone administration in both groups. The power calculation is based on a non-inferiority analysis with an expected OPR in both groups of 44% and the upper limit of a one-sided 95% CI will exclude a difference in favour of the control group of more than 10.0%. An interim analysis will be conducted once half of the study population has been enrolled.
ETHICS AND DISSEMINATION
The trial was approved on 21 November 2023 by the Danish National Ethical Committee and the Danish Medicines Agency and is authorised by the Clinical Trials Information System (EUCT number 2023-504616-15-02). All patients will provide informed consent before being enrolled in the study. The results will be published in an international journal.
TRIAL REGISTRATION NUMBER
EUCT number: 2023-504616-15-02.
Topics: Humans; Female; Progesterone; Embryo Transfer; Administration, Intravaginal; Luteal Phase; Pregnancy; Pregnancy Rate; Cryopreservation; Administration, Rectal; Hormone Replacement Therapy; Progestins; Adult; Denmark; Equivalence Trials as Topic
PubMed: 38960462
DOI: 10.1136/bmjopen-2023-082879 -
Journal of Molecular and Cellular... Jul 2024Coronary heart disease (CHD) is a prevalent cardiac disease that causes over 370,000 deaths annually in the USA. In CHD, occlusion of a coronary artery causes ischemia...
Coronary heart disease (CHD) is a prevalent cardiac disease that causes over 370,000 deaths annually in the USA. In CHD, occlusion of a coronary artery causes ischemia of the cardiac muscle, which results in myocardial infarction (MI). Junctophilin-2 (JPH2) is a membrane protein that ensures efficient calcium handling and proper excitation-contraction coupling. Studies have identified loss of JPH2 due to calpain-mediated proteolysis as a key pathogenic event in ischemia-induced heart failure (HF). Our findings show that calpain-2-mediated JPH2 cleavage yields increased levels of a C-terminal cleaved peptide (JPH2-CTP) in patients with ischemic cardiomyopathy and mice with experimental MI. We created a novel knock-in mouse model by removing residues 479-SPAGTPPQ-486 to prevent calpain-2-mediated cleavage at this site. Functional and molecular assessment of cardiac function post-MI in cleavage site deletion (CSD) mice showed preserved cardiac contractility and reduced dilation, reduced JPH2-CTP levels, attenuated adverse remodeling, improved T-tubular structure, and normalized SR Ca-handling. Adenovirus mediated calpain-2 knockdown in mice exhibited similar findings. Pulldown of CTP followed by proteomic analysis revealed valosin-containing protein (VCP) and BAG family molecular chaperone regulator 3 (BAG3) as novel binding partners of JPH2. Together, our findings suggest that blocking calpain-2-mediated JPH2 cleavage may be a promising new strategy for delaying the development of HF following MI.
PubMed: 38960317
DOI: 10.1016/j.yjmcc.2024.06.011 -
World Neurosurgery Jul 2024Remarkable innovations in spinal endoscopic surgery have broadened its applications over the past 20 years. Full-endoscopic fusions have been widely reported, and...
Remarkable innovations in spinal endoscopic surgery have broadened its applications over the past 20 years. Full-endoscopic fusions have been widely reported, and several full-endoscopic approaches for interbody fusion have been published. In general, full-endoscopic lumbar interbody fusion (LIF) is called Endo-LIF, and facet-preserving endo-LIF through the transforaminal route is called trans-Kambin's triangle LIF, which has a relatively longer history than facet-sacrificing endo-LIF via the posterolateral route. Both approaches can reduce intraoperative and postoperative bleeding. However, there is a higher risk of subsidence and exit nerve root injury. There is no direct decompression in either of the interbody fusions, and additional decompression is required if there is severe lumbar bony canal stenosis. However, the posterior interlaminar approach, which is a well-known standard in full-endoscopic spine surgery, has rarely been applied in the field of endoscopic lumbar fusion surgery. Full-endoscopic posterior LIF (FE-PLIF) via an interlaminar approach can accomplish direct decompression of bony canal stenosis and safe interbody fusion. FE-PLIF via an interlaminar approach demonstrated a longer operation time, less blood loss, and shorter hospitalization duration than minimally invasive transforaminal LIF. FE-PLIF, which can accomplish direct decompression for bony spinal canal stenosis, is superior to other Endo-LIFs. However, FE-PLIF requires technical dexterity to improve efficiency and reduce technical complexity.
PubMed: 38960311
DOI: 10.1016/j.wneu.2024.06.147