Kirschner Wire Prying and Leverage Technique: a new closed reduction method in treatment of pediatric "Irreducible Supracondylar Humerus Fractures".

BACKGROUND: This study employs an innovative closed reduction approach to treat pediatric "Irreducible Supracondylar Humerus Fractures" with the goal of demonstrating its practical application compared to conventional methods. METHODS: This study sampled 146 surgically treated cases of "Irreducible Supracondylar Humerus Fractures" in our department. After applying inclusion and exclusion criteria, 120 children were selected and divided into two groups based on treatment methods. Group 1 underwent Closed Reduction and Percutaneous Pinning (CRPP), while Group 2 received treatment using the Kirschner Wire Prying and Leverage Technique alongside CRPP. The relevant data to the study were collected and assessed during the follow-up period. RESULTS: Results indicate that Group 2 demonstrated significantly shorter operative times and fewer instances of intraoperative fluoroscopy compared to Group 1. Furthermore, the percentage of cases requiring open reduction was notably higher in Group 1 than in Group 2. The analysis also identified age, BMI, time from injury to surgery, and the initial deviation of the distal fragment as independent risk factors associated with the failure of closed reduction. The integration of CRPP with the Kirschner Wire Prying and Leverage Technique emerges as a safe and effective strategy for managing "Irreducible Supracondylar Humerus Fractures." This innovative approach not only reduces operative time and intraoperative fluoroscopy needs but also diminishes the reliance on open reduction without compromising safety.

In-hospital prognosis of acute ST-elevation myocardial infarction in patients with recent recreational drug use.

AIMS: Although recreational drug use may induce ST-elevated myocardial infarction (STEMI), its prevalence in patients hospitalized in intensive cardiac care units (ICCUs), as well as its short-term cardiovascular consequences, remains unknown. We aimed to assess the in-hospital prognosis of STEMI in patients with recreational drug use from the ADDICT-ICCU study. METHODS AND RESULTS: From 7-22 April 2021, recreational drug use was detected prospectively by a systematic urine multidrug test in all consecutive patients admitted for STEMI in 39 ICCUs across France. The primary endpoint was major adverse cardiac events (MACEs) defined by death, resuscitated cardiac arrest, or cardiogenic shock. Among the 325 patients (age 62 ± 13 years, 79% men), 41 (12.6%) had a positive multidrug test (cannabis: 11.1%, opioids: 4.6%, cocaine: 1.2%, 3,4-methylenedioxymethamphetamine: 0.6%). The prevalence increased to 34.0% in patients under 50 years of age. Recreational drug users were more frequently men (93% vs. 77%, p = 0.02), younger (50 ± 12 years vs. 63 ± 13 years, P < 0.001), and more active smokers (78% vs. 34%, P < 0.001). During hospitalization, 17 MACEs occurred (5.2%), including 6 deaths (1.8%), 10 cardiogenic shocks (3.1%), and 7 resuscitated cardiac arrests (2.2%). Major adverse cardiac events (17.1% vs. 3.5%, P < 0.001) and ventricular arrhythmia (9.8% vs. 1.4%, P = 0.01) were more frequent in recreational drug users. Use of recreational drugs was associated with more MACEs after adjustment for comorbidities (odds ratio = 13.1; 95% confidence interval: 3.4-54.6). CONCLUSION: In patients with STEMI, recreational drug use is prevalent, especially in patients under 50 years of age, and is independently associated with an increase of MACEs with more ventricular arrhythmia. TRIAL REGISTRATION: URL: https://clinicaltrials.gov/ct2/show/NCT05063097.

The importance of preconception Hcy testing: identification of a folate trap syndrome in a woman attending an assisted reproduction program.

Methylation is a ubiquitous and permanent key biochemical process playing a major role in gametogenesis and embryogenesis in relation to epigenetics and imprinting. Methylation relies on a unique cofactor S-Adenosyl Methionine: SAM. Release of the methyl group onto target molecules is followed by liberation of S-Adenosyl Homocysteine (SAH), and then homocysteine (Hcy), both potent inhibitors of the methylation process. Defective recycling of homocysteine, leading to Hyperhomocysteinemia, is mainly due to reduced activity of MTHFR (Methylene TetraHydroFolate Reductase). However, we described here, in a woman attending an ART program, a rather rare syndrome: The Folate trap syndrome. Due to vitamin B12 deficiency (malabsorption), Hcy cannot be recycled to methionine by the methionine synthase. Transmethylation activity is weak and leads to Hhcy (Hyperhomocysteinhemia). Her Hhcy, over 16µM, was resistant to 5MTHF (5 Methyltetrahydrofolate) associated with a support of the one carbon cycle, a classical efficient treatment for elevated homocysteine. Treatment with Methylcobalamine (associated with adenosyl Cobalamine) allowed a Hcy drop down to 10 µM. Knowing the pleiotropic negative impact of Hcy on gametes, embryos and pregnancy in general, we strongly recommend a Hcy dosage in both members of couples seeking treatment for pregnancy.

Hyperhomocysteinemia in hypofertile male patients can be alleviated by supplementation with 5MTHF associated with one carbon cycle support.

Introduction: Homocysteine (Hcy) is a cellular poison, side product of the hydrolysis of S-Adenosyl Homocysteine, produced after the universal methylation effector S -Adenosylmethionine liberates a methyl group to recipient targets. It inhibits the methylation processes and its rising is associated with multiple disease states and ultimately is both a cause and a consequence of oxidative stress, affecting male gametogenesis. We have determined hyper homocysteinhemia (HHcy) levels can be reliably reduced in hypofertile patients in order to decrease/avoid associated epigenetic problems and protect the health of future children, in consideration of the fact that treatment with high doses of folic acid is inappropriate. Methods: Homocysteine levels were screened in male patients consulting for long-standing infertility associated with at least three failed Assisted Reproductive Technology (ART) attempts and/or repeat miscarriages. Seventy-seven patients with Hcy levels > 15 µM were treated for three months with a combination of micronutrients including 5- MethylTetraHydroFolate (5-MTHF), the compound downstream to the MTHFR enzyme, to support the one carbon cycle; re-testing was performed at the end of a 3 months treatment period. Genetic status for Methylenetetrahydrofolate Reductase (MTHFR) Single nucleotide polymorphisms (SNPs) 677CT (c.6777C > T) and 1298AC (c.1298A > C) was determined. Results: Micronutrients/5-MTHF were highly efficient in decreasing circulating Hcy, from averages 27.4 to 10.7 µM, with a mean observed decrease of 16.7 µM. The MTHFR SNP 677TT (homozygous form) and combined heterozygous 677CT/1298AC status represent 77.9% of the patients with elevated Hcy. Discussion: Estimation HHcy should not be overlooked in men suffering infertility of long duration. MTHFR SNPs, especially 677TT, are a major cause of high homocysteinhemia (HHcy). In these hypofertile patients, treatment with micronutrients including 5-MTHF reduces Hcy and even allows spontaneous pregnancies post treatment. This type of therapy should be considered in order to ensure these patients' quality of life and avoid future epigenetic problems in their descendants.

[Recreative drug use and cardiovascular disease]. / Consommation de drogues récréatives et pathologies cardiovasculaires.

Widely spread, and continuously increasing, recreational drug use in general population has been associated with cardiovascular events, as illustrated by clinical studies and supported by a pathophysiological rationale. Understanding the cardiovascular effects of drugs, screening, and secondary prevention are crucial components in the management of those patients in cardiology.

MTHFR SNPs (Methyl Tetrahydrofolate Reductase, Single Nucleotide Polymorphisms) C677T and A1298C Prevalence and Serum Homocysteine Levels in >2100 Hypofertile Caucasian Male Patients

Methylation is a crucially important ubiquitous biochemical process, which covalently adds methyl groups to a variety of molecular targets. It is the key regulatory process that determines the acquisition of imprinting and epigenetic marks during gametogenesis. Methylation processes are dependent upon two metabolic cycles, the folates and the one-carbon cycles. The activity of these two cycles is compromised by single nucleotide polymorphisms (SNPs) in the gene encoding the Methylenetetrahydrofolate reductase (MTHFR) enzyme. These SNPs affect spermatogenesis and oocyte maturation, creating cytologic/chromosomal anomalies. The two main MTHFR SNP variants C677T (c.6777C>T) and A1298C (c.1298A>C) together with serum homocysteine levels were tested in men with >3 years' duration of infertility who had failed several ART attempts with the same partner. These patients are often classified as having "idiopathic infertility". We observed that the genetic status with highest prevalence in this group is the heterozygous C677T, followed by the combined heterozygous C677T/A1298C, and then A1298C; these three variants represent 65% of our population. Only 13.1% of the patients tested are wild type (WT), C677C/A1298A). The homozygous 677TT and the combined heterozygote 677CT/1298AC groups have the highest percentage of patients with an elevated circulating homocysteine level of >15 µMolar (57.8% and 18.8%, respectively, which is highly significant for both). Elevated homocysteine is known to be detrimental to spermatogenesis, and the population with this parameter is not marginal. In conclusion, determination of these two SNPs and serum homocysteine should not be overlooked for patients with severe infertility of long duration, including those with repeated miscarriages. Patients must also be informed about pleiotropic medical implications relevant to their own health, as well as to the health of future children.

Biochemical Hazards during Three Phases of Assisted Reproductive Technology: Repercussions Associated with Epigenesis and Imprinting.

Medically assisted reproduction, now considered a routine, successful treatment for infertility worldwide, has produced at least 8 million live births. However, a growing body of evidence is pointing toward an increased incidence of epigenetic/imprinting disorders in the offspring, raising concern that the techniques involved may have an impact on crucial stages of early embryo and fetal development highly vulnerable to epigenetic influence. In this paper, the key role of methylation processes in epigenesis, namely the essential biochemical/metabolic pathways involving folates and one-carbon cycles necessary for correct DNA/histone methylation, is discussed. Furthermore, potential contributors to epigenetics dysregulation during the three phases of assisted reproduction: preparation for and controlled ovarian hyperstimulation (COH); methylation processes during the preimplantation embryo culture stages; the effects of unmetabolized folic acid (UMFA) during embryogenesis on imprinting methyl "tags", are described. Advances in technology have opened a window into developmental processes that were previously inaccessible to research: it is now clear that ART procedures have the potential to influence DNA methylation in embryonic and fetal life, with an impact on health and disease risk in future generations. Critical re-evaluation of protocols and procedures is now an urgent priority, with a focus on interventions targeted toward improving ART procedures, with special attention to in vitro culture protocols and the effects of excessive folic acid intake.

T677T Methylenetetrahydrofolate Reductase Single Nucleotide Polymorphisms Increased Prevalence in a Subgroup of Infertile Patients with Endometriosis.

Background: Approximately 10% (190 million) of women worldwide are affected by endometriosis, ectopic deposits of endometrial tissue that create a major source of pain that affects lifestyle and reproductive function. The pathogenesis of endometriosis is an estrogen-dependent inflammatory process, influenced/catalyzed by oxidative stress and consequently defective methylation, with biochemical features centered around the folate and one-carbon cycles. We aimed to determine whether a link could be found between the two major methylenetetrahydrofolate reductase single nucleotide polymorphisms (MTHFR SNPs), c.677C>T and c.1298A>C, involved in methylation process/epigenetic marking failures, and endometriosis. Material and Methods: We studied a population of 158 patients in a group of >1500 referred for treatment of infertility. All the patients had experienced >2 failed assisted reproductive technology cycles and/or >2 miscarriages, a classical cohort for investigation in our group. Patients with endometriosis had at least stage 2+ disease confirmed by laparoscopy. Results: The prevalence of the homozygous c.677C>T isoform is doubled in the endometriosis group, 21.5% versus 10.2% in the non-endometriosis group (p > 0.01). Symmetrically, the percentage of patients in the endometriosis group with the wild type MTHFR significantly decreased by one-half (8.2%-17.2%) in the non-endometriosis group (p < 0.001). Conclusion: Determination of MTHFR c.677C>T should not be overlooked in patients with harmful endometriosis affecting their fertility. As folates metabolism is impaired in these MTHFR SNPs carrier patients, co-treatment with 5-methyl folate may constitute a successful (co)-treatment modality.

Folic Acid, Folinic Acid, 5 Methyl TetraHydroFolate Supplementation for Mutations That Affect Epigenesis through the Folate and One-Carbon Cycles.

Methylation is an essential biochemical mechanism that is central to the transmission of life, and crucially responsible for regulating gametogenesis and continued embryo development. The methylation of DNA and histones drives cell division and regulation of gene expression through epigenesis and imprinting. Brain development and its maturation also depend on correct lipid methylation, and continued neuronal function depends on biogenic amines that require methylation for their synthesis. All methylation processes are carried out via a methyltransferase enzyme and its unique co-factor S-adenosylmethionine (SAM); the transfer of a methyl group to a target molecule results in the release of SAH (SA homocysteine), and then homocysteine (Hcy). Both of these molecules are toxic, inhibiting methylation in a variety of ways, and Hcy recycling to methionine is imperative; this is achieved via the one carbon cycle, supported by the folates cycle. Folate deficiency causes hyperhomocysteinaemia, with several associated diseases; during early pregnancy, deficiency interferes with closure of the neural tube at the fourth week of gestation, and nutraceutical supplementation has been routinely prescribed to prevent neural tube defects, mainly involving B vitamins, Zn and folates. The two metabolic pathways are subject to single nucleotide polymorphisms that alter their activity/capacity, often severely, impairing specific physiological functions including fertility, brain and cardiac function. The impact of three types of nutraceutical supplements, folic acid (FA), folinic acid (FLA) and 5 Methyl THF (MTHF), will be discussed here, with their positive effects alongside potentially hazardous secondary effects. The issue surrounding FA and its association with UMFA (unmetabolized folic acid) syndrome is now a matter of concern, as UMFA is currently found in the umbilical cord of the fetus, and even in infants' blood. We will discuss its putative role in influencing the acquisition of epigenetic marks in the germline, acquired during embryogenesis, as well as the role of FA in the management of cancerous disease.

A Rare Chromosome Rearrangement Leading to de la Chapelle Syndrome with a Mosaic 45,X Cell Line: (46,X,psu dic(X;Y)(p22.13;q11.221)/45,X/45,psu dic(X;Y)(p22.13;q11.221).

Infertility affects about 15% of couples of childbearing age. About half of these cases can be attributed predominantly to a male factor, such as a quantitative or qualitative impairment in spermatogenesis. The first-line genetic screening for non-obstructive azoospermia is limited to karyotyping (to identify chromosome abnormalities) and Y chromosome microdeletions screening, with a view to explaining the spermatogenetic failure and evaluating the likelihood of sperm retrieval in a testicular biopsy. For patients with de la Chapelle syndrome (a 46,XX karyotype with the presence of SRY (Sex determining region Y) gene) and/or Y chromosome microdeletions, or sex chromosome mosaicism, sperm retrieval is usually unsuccessful. Here, we report a patient with de la Chapelle syndrome and a short stature caused by mosaicism and a very rare chromosome rearrangement: mos 46,X,psu dic(X;Y)/45,X/45,psu dic(X;Y). This case indicates that in de la Chapelle syndrome, X- and Y-chromosome breakpoint variability is high.

MTHFR (methylenetetrahydrofolate reductase: EC 1.5.1.20) SNPs (single-nucleotide polymorphisms) and homocysteine in patients referred for investigation of fertility.

PURPOSE: MTHFR, one of the major enzymes in the folate cycle, is known to acquire single-nucleotide polymorphisms that significantly reduce its activity, resulting in an increase in circulating homocysteine. Methylation processes are of crucial importance in gametogenesis, involved in the regulation of imprinting and epigenetic tags on DNA and histones. We have retrospectively assessed the prevalence of MTHFR SNPs in a population consulting for infertility according to gender and studied the impact of the mutations on circulating homocysteine levels. METHODS: More than 2900 patients having suffered at least two miscarriages (2 to 9) or two failed IVF/ICSI (2 to 10) attempts were included for analysis of MTHFR SNPs C677T and A1298C. Serum homocysteine levels were measured simultaneously. RESULTS: We observed no difference in the prevalence of different genetic backgrounds between men and women; only 15% of the patients were found to be wild type. More than 40% of the patients are either homozygous for one SNP or compound heterozygous carriers. As expected, the C677T SNP shows the greatest adverse effect on homocysteine accumulation. The impact of MTHFR SNPs on circulating homocysteine is different in men than in women. CONCLUSIONS: Determination of MTHFR SNPs in both men and women must be seriously advocated in the presence of long-standing infertility; male gametes, from MTHFR SNPs carriers, are not exempted from exerting a hazardous impact on fertility. Patients should be informed of the pleiotropic medical implications of these SNPs for their own health, as well as for the health of future children.

Methylation: An Ineluctable Biochemical and Physiological Process Essential to the Transmission of Life.

Methylation is a universal biochemical process which covalently adds methyl groups to a variety of molecular targets. It plays a critical role in two major global regulatory mechanisms, epigenetic modifications and imprinting, via methyl tagging on histones and DNA. During reproduction, the two genomes that unite to create a new individual are complementary but not equivalent. Methylation determines the complementary regulatory characteristics of male and female genomes. DNA methylation is executed by methyltransferases that transfer a methyl group from S-adenosylmethionine, the universal methyl donor, to cytosine residues of CG (also designated CpG). Histones are methylated mainly on lysine and arginine residues. The methylation processes regulate the main steps in reproductive physiology: gametogenesis, and early and late embryo development. A focus will be made on the impact of assisted reproductive technology and on the impact of endocrine disruptors (EDCs) via generation of oxidative stress.

5-Methyltetrahydrofolate reduces blood homocysteine level significantly in C677T methyltetrahydrofolate reductase single-nucleotide polymorphism carriers consulting for infertility.

PURPOSE: Methyltetrahydrofolate reductase (MTHFR) C677T (ala222Val) is a single-nucleotide polymorphism (SNP) that affects the formation of 5-methyltetrahydrofolate (5-MTHF), the active folate that allows the recycling of homocysteine (Hcy) to Methionine. Hcy is at the epicentre of oxidative stress and DNA methylation errors. This SNP often increases the circulating Hcy levels and consequently reduces the methylation process, which is involved in the epigenesis and imprinting of markings in gametes. This study aimed to investigate decreases in Hcy levels in MTHFR SNP carriers. PROCEDURE: Eighty-nine couples with fertility problems for at least 3 years were included in this program. The women were systematically tested for the MTHFR C 677T isoform. If the woman tested positive, testing of the male partner was proposed. All the carriers had well-controlled blood Hcy levels before and after treatment (600µg of 5-MTHF/day, with a backup of one carbon cycle during at least 3 months). FINDINGS: As expected, the circulating Hcy level was higher in the homozygous patients than in the heterozygous and wild-type patients. The treatments caused a significant decrease of the circulating Hcy in the SNP carriers group. CONCLUSIONS: Couples with a long history of infertility should be analysed for MTHFR SNP and homocysteine and should be treated with physiological doses of 5-MTHF instead of high doses of folic acid.

High doses of folic acid induce a pseudo-methylenetetrahydrofolate syndrome.

A 41-year-old Caucasian woman with a history of infertility dating from 2011 was identified as wild-type (no mutations) for methylenetetrahydrofolate reductase single nucleotide polymorphisms (MTHFR-SNPs). Previous treatment included three failed in vitro fertilization/intracytoplasmic sperm injection cycles as well as one failed cycle of in vitro fertilization/intracytoplasmic sperm injection with donated oocytes. Counseling for a further oocyte donation cycle included advice to take high doses of folic acid (5 mG per day). Prior to initiation of this cycle, in October 2017 she attended our unit for general gynecological assessment and was found to have a slightly increased level of homocysteine, 12.2 µmol/L. A further test in February 2018 showed an increase to 17.2 µmol/L. Folic acid was stopped, and she was treated with 5-MTHF (500 µG daily), which supports the one-carbon cycle. After 5 days of treatment, her homocysteine level dropped to a baseline level of 8.2 µmol/L. As previously described in mice, high doses of folic acid can induce a "pseudo MTHFR" syndrome in wild-type patients, leading to an elevated unmetabolized folic acid syndrome which results in increased serum levels of homocysteine.

Association between the MTHFR-C677T isoform and structure of sperm DNA.

PURPOSE: The aim of this study is to evaluate whether the MTHFR contribution to male decreased fertility can be attributable to anomalies in sperm nucleus DNA structure in relation to defective methylation. METHODS: The presence of MTHFR C677T, contributing at most for male infertility, was determined from a venous blood sample, using real-time polymerase chain reaction (PCR). Sperm DNA fragmentation (SDF) and sperm nucleus decondensation index (SDI) measurements were performed using acridine orange and flow cytometry. SDF and SDI of men MTHFR C677T heterozygous or homozygous were compared to a general population of hypo-fertile patients RESULTS: SDF is not increased either in homozygous or heterozygous carriers of MTHFR C677T. In contrast, SDI is increased with a higher incidence in homozygous (p = 0.0006) than in heterozygous (p = 0.029) patients when compared with the control population. Using a critical threshold of 20% for either SDI or SDF assayed with our technique, the percentage of patients with results higher than this value is not significant with respect to fragmentation (0.128), but is significantly increased for decondensation (0.0003). CONCLUSIONS: Defective methylation linked to MTHFR may contribute to sperm pathogenesis via increased SDI. After DNA structure analysis, especially SDI, treatment with 5-methyl tetrahydrofolate (MTHF), the metabolite downstream from the action of MTHFR, should be recommended as a therapeutic approach. Patients with a high SDI should be tested for MTHFR isoforms as part of a healthcare policy.

Developmental reorganization of the output of a GABAergic interneuronal circuit.

Locally projecting inhibitory interneurons play a crucial role in the patterning and timing of network activity. However, because of their relative inaccessibility, little is known about their development or incorporation into circuits. In this report we demonstrate that the GABAergic R-interneuron circuit undergoes a reorganization in the chick embryo spinal cord between embryonic days 8 and 15 (E8 and E15). R-interneurons receive synaptic input from and project back to motoneurons. By stimulating motoneurons projecting in one ventral root and recording the disynaptic response from motoneurons in adjacent segments, we show that the output of the R-interneuron circuit is reorganized during development. After stimulation of the LS2 ventral root, disynaptic responses observed in whole cell recordings became more common and stronger for LS3 motoneurons and less common for the more distant LS4 motoneurons from E8 to E10. Optical studies demonstrated that R-interneurons activated by LS2 stimulation were restricted to the LS2 segment and had a small glutamatergic component at both E8 and E10, but that more R-interneurons were activated within the segment by E10. The recruitment of more LS2 R-interneurons at E10 is likely to contribute to stronger projections to LS3 motoneurons, but the fact that fewer LS4 motoneurons receive this input is more consistent with a functional refinement of the more distant projection of the GABAergic R-interneuron. Interestingly, this pattern of reorganization was not observed throughout the rostrocaudal extent of the cord, introducing the possibility that refinement could serve to remove connections between functionally unrelated interneurons and motoneurons.