The objective of this study is to synthesize the available literature of in vivo animal studies and human clinical trials on the association between the AA pathway and male fertility. PGE is significantly decreased in the semen of infertile men, suggesting the potential for exploitation of PGE agonists to improve male fertility. Indeed, ibuprofen can affect male fertility by promoting alterations in sperm function and standard semen parameters. The results showed that targeting the AA pathways could be an attractive strategy for the treatment of male fertility.Arachidonic acid (AA) is a polyunsaturated fatty acid that is involved in male fertility. Human seminal fluid contains different prostaglandins: PGE (PGE Reactive oxygen species (ROS) and cytokines can also activate PLA2. The most known pathway of AA is the cyclooxygenase (COX) pathway which is responsible for the production of prostaglandins (PGs) and thromboxane (TX). The lipoxygenases (LOs) pathway brings to the production of both, leukotrienes (LT) and anti-inflammatory lipoxins (LXs) (Arachidonic acid (AA) is a polyunsaturated fatty acid released by the activation of phospholipase Ans (LXs)  1]. Cyt. Cyt2 (P1 and PGE2), PGF2α, and their specific 19-hydroxy derivatives, 18,19-dehydro derivatives of PGE1 and PGE2. PGE2 and 19-hydroxy PGE (19-OH PGE) are the main PGs present in semen [2 are 15 to 25 times higher in the lumen of ram cauda epididymidis in respect to rete testis. In washed sperm recovered from the vas deferens of rams PGE2 increases the sperm cyclic adenosine monophosphate (cAMP) [2+ into the cell [2 can regulate epithelial apoptosis [2 (PGD2) is abundant in the seminal fluid of fertile men, and is significantly decreased in the semen of oligozoospermic men [Von Euler in the earliest 1930s was the first to report the presence of PGs in the seminal plasma. They were thought to originate from the prostate gland, and for this reason they were named prostaglandins . The PGsin semen . PGs conin semen . Seminalin semen , with adin semen . Ollero in semen . Cosentie (cAMP) . It is sthe cell . PGE canthe cell . Anotherthe cell . PGD2 capoptosis . Lipocalrmic men . L-PGDS rmic men . In addirmic men . Schell rmic men . There armic men . 15(S)-lrmic men ,24. The This systematic review followed the preferred reporting items for systematic reviews (PRISMA) guidelines.We conducted a systematic review to report all the findings of in vivo animal studies and human clinical trials on the association between AA pathways and male fertility.The eligibility criteria for inclusion were: All Randomized Controlled Trials (RCTs), or observational studies (cohort or case control design) reporting the association of the AA pathway with male fertility. We excluded reviews, and studies on the association of AA pathways with female fertility. The literature search was not restricted by the year of publication.We collected all the relevant data that conformed to the eligibility criteria on the role of the AA pathway in male fertility. We searched in Pubmed, Scopus, Medline, and Embase databases all studies reporting the association between arachidonic acid mediators and male fertility using the following text words; “arachidonic acid and male fertility”; “prostaglandin and male fertility”; “thromboxane and male fertility”; “leukotriene and male fertility”;“lipoxin and male fertility”; “5-lipoxygenase and male fertility”; “12-lipoxygenase and male fertility”; “15-lipoxygenase and male fertility”; “pro-resolving lipid mediators and male fertility”; “cytochrome P450 epoxygenase pathway and male fertility”. Only studies that fulfilled the eligibility criteria were included.Only 68 articles out of 456 identified articles, were included in this systematic review.Duplicates articles, studies that did not report the association of AA pathways with male fertility, reviews, and original articles reporting AA pathways and female fertility were excluded.The findings were classified in three tables, reporting findings from animal studies, human studies, and studies on the potential effects of NSAIDs in seminal PGs. One article was placed in more than one table because it contains data from animal study, and data on the effects of NSAIDs  in seminal prostaglandins.A schematic diagram of the literature search procedure is shown in 1, PGE2, PGF2α, sPLA2, PGDS).As shown in 2 is a fertility-associated biomarker in seminal plasma and serum. Group VIA Phospholipase A2 (iPLA2β) has an important role in spermatozoa [A study conducted in dromedary camels showed that sPLArmatozoa . Data shrmatozoa . Fouchécrmatozoa .Acsl6−/−) male mice testes [Acsl6 knockout (Acsl6−/−) male mice were severely subfertile with reduced sperm counts and smaller testes [Higher levels of AA were found in Acsl6 (long-chain acyl-CoA synthetase 6) knockout  did not have any local effect on epididymal spermatozoa fertilizing capacity, despite reducing the weight of the injected testis due to blood flow restriction at the site of application. Considering that PGs suppress steroidogenesis by lowering the plasma levels of androgens, the incapacity of PGs to affect the fertilizing capacity of spermatozoa in both injected and contralateral sides suggests that the androgen that has been available following the treatment schedule was enough to keep the fertilizing capacity of the epididymal spermatozoa despite of the PGs site of injection [2α, or PGE1 had no effect on fertilizing capacity [1 and PGE2 maintained both the fertilizing capacity of epididymal spermatozoa, and the weight of accessory sex glands [2 in testes can modify the effect of trophic hormones and prevent the impairment of fertility in rats [2 and PGF2α [2α can suppress testosterone production in the testes [PGEal fluid . Differeal fluid ,34. Intes weight . Both PGnjection . Howevernjection . The shocapacity ,37. Testx glands . Hafiez  in rats . The pland PGF2α . 15-Me-Pe testes .1, PGE2, PGF2α), could be explained by the restricted blood flow through the testes following the local application of PGs [The testicular regression observed in the injected testis  were found in the interstitial cells of men with impaired spermatogenesis [PGDogenesis . Chen etogenesis .2-isoprostanes (F2-IsoPs) are produced by the oxygenation of AA, and are related to male infertility, as a marker of sperm immaturity by affecting sperm quality [2-IsoPlevels and sperm immaturity [2-IsoPs semen levels in fertile and infertile men, and reported that F2-IsoP levels above 29.96 ng/mL are potentially related to idiopathic infertility and other pathological conditions, and can serve as an index of altered sperm quality in infertile patients [F quality ,60. In imaturity . Recentlpatients . Insteadpatients . High lepatients .However other controversial studies demonstrated no correlation between seminal PGs concentration and sperm morphology, motility, concentration, and fertility ,65. DorpThe main characteristics of the NSAIDs’ role in seminal fluid PGs and male fertility that were systematically reviewed are summarized in 2α, 8ß-19-hydroxy-PGF1α) were reduced in semen samples of six volunteers before, during and after treatment with naproxen 250 mg 3 times daily for 2 weeks [Bendvold et al. showed that all PGs  showed that the pre-pubertal treatment with ibuprofen had a negative effect on sperm quality and quantity, which affects reproduction . The mal2 levels in seminal fluid in rats, suggesting that these compounds can be used to control male fertility [NSAIDs  decreased the PGEertility . The redertility .Interestingly, Conte et al., showed that indomethacin improved significantly the sperm count and motility in infertile oligozoospermic patients with high levels of PGs . The numOur research study included 17 studies carried out in animals, 31 studies conducted in humans, and 21 studies that reported the association between NSAIDs and seminal fluid PGs. One of the articles was inserted in both 2 enzyme is also a major component in sperm [Various evidence has shown that the AA pathway and its mediators are involved in male fertility. Starting from AA, studies demonstrated that AA itself can mediate the stimulatory effect of luteinizing hormone on the synthesis of testicular steroids ,89. PLA2in sperm . COX-2 iin sperm .Human seminal fluid contains different prostaglandins that originate from the seminal vesicles, and play important roles in sperm function, and motility. They can act directly on spermatozoa through the PG receptors ,91, and PGE is one of the main PGs assessed in male fertility in both animal and human clinical studies, suggesting that the semen of infertile men has lower levels of PGE . Based o2 synthase is also expressed in patients with impaired spermatogenesis. Its levels are reduced in oligozoospermic men [2 was found in patients with idiopathic infertility [Despite PGE, hematopoietic PGDrmic men . Analogoertility .Targeting the AA pathway has emerged as an attractive strategy for the treatment of male fertility. Ibuprofen can affect fertility through the alteration of sperm motility, function, viability, count potentially through the reduction of PGS synthesis ,94,95,96In addition, other NSAIDs such as flurbiprofen, acetylsalicylic acid, naproxen can decrease PG levels in human semen and increase fertility ,69,70,83Chronic treatment  with acetylsalicylic acid in male mice , or treaThe subchronic dose of aspirin (12.5 mg/kg for 30 days and 60 days) given to male rats changed the reproductive profile of male rats, and reduced sperm mobility and density . In lineTo our knowledge, this is the first study reporting and evaluating all the published studies on the association of AA pathways mediators and male fertility. Of notice, most of the references are old, and only few studies have been performed recently in the field. Studies reported in this article are not homogeneous, and often report conflicting results. However, we believe that based on the promising results from either animal or human studies, it is the duty of the academic world to keep exploring the AA pathway’s implication in male fertility. Considering that PGE is the main PG involved in male fertility, and its levels are decreased in the semen of infertile men, the PGE agonist, or any drug which causes an increase in seminal PGE concentration could be suggested as a potential approach to improve male fertility. In addition, we notice that there is no information on the role of leuokotrienes, or lipoxins in semen, and on the role of sperm motility, morphology, function, and fertility. Additional studies should be carried out to further explore other AA pathways mediators, or enzymes. In addition, long term effect of NSAIDs in male fertility should be further explored. Considering that COX-2 is expressed in the testes of infertile men and is implicated in testicular inflammation related to idiopathic infertility it would be interesting assessing also the role of COXIBs in male fertility.We believe that despite some controversial results targeting the AA pathway is a promising strategy to be further explored for expanding treatment options for male infertility.


Wnt signaling plays an important role in regulating the biological behavior of cancers, and many drugs targeting this signaling have been developed. Recently, a series of research have revealed that Wnt signaling could regulate DNA damage response (DDR) which is crucial for maintaining the genomic integrity in cells and closely related to cancer genome instability. Many drugs have been developed to target DNA damage response in cancers. Notably, different components of the Wnt and DDR pathways are involved in crosstalk, forming a complex regulatory network and providing new opportunities for cancer therapy. Here, we provide a brief overview of Wnt signaling and DDR in the field of cancer research and review the interactions between these two pathways. Finally, we also discuss the possibility of therapeutic agents targeting Wnt and DDR as potential cancer treatment strategies. The Wnt signaling pathway is a complex protein regulatory network cascade, which participates in various biological processes, including embryonic development, tissue development and regeneration, and cancer development and progression. The abnormal activation of Wnt signaling will result in many pathological processes, such as cancer, inflammatory and immune diseases, and metabolic diseases .DNA damage response (DDR) is a hierarchical signaling pathway that functions to maintain the genome integrity and stability and is coordinated by a variety of proteins. Numerous studies have demonstrated that DDR deficiency is closely associated with several diseases , among wPrevious studies have reported that Wnt signaling can affect DDR by regulating a variety of factors . In this2+  pathway and Wnt/PCP (planar cell polarity) pathway) pathways  family receptors, low-density lipoprotein receptor-related protein 5/6 (LRP5/6), and receptor tyrosine kinase-like orphan receptors (ROR1/2). Wnt signaling activation leads to transcriptional activation of multiple downstream effectors , and extpathways . Generalpathways .The key members of the canonical Wnt signaling pathway include the Wnt family proteins, FZD/LRP6, disheveled protein (Dvl), β-catenin, T lymphocytokine/lymphoenhancer factor (TCF), human lymphoid enhancer factor (LEF), and the β-catenin destruction complex which comprises adenomatous polyposis coli (APC), axin, glycogen synthase kinase-3β (GSK-3β), and casein kinase 1α (CK1α). In the absence of a Wnt signal, β-catenin binds to the destruction complex, resulting in its ubiquitination via proteasomal degradation mediated by β-TrCP. In the presence of Wnt signal, Wnt binds to the FZD and LRP5/6 receptors to activate Dvl protein and inhibit the destruction complex, resulting in the accumulation of free unphosphorylated β-catenin in the cytoplasm, which is then transported to the nucleus where it can combine with TCF/LEF to induce transcription of downstream Wnt signaling genes .2+, reduced cyclic guanosine (cGMP) levels, and activation of Ca2+/calmodulin-dependent protein kinase-II (CaMKII) and PKC; these processes can stimulate NFAT and other transcription factors such as CREB1 , nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination , and non-homologous end-joining . HR and NHEJ are the main repair ways for double-strand breaks (DSBs). HR always occurs in G2 and S phases, during which sister chromatids are present and can provide a template strand, while NHEJ is cell cycle phase-independent. For eukaryotes, NHEJ repairs most DSBs, and HR is preferentially used when the lesion occurs at DNA replication forks.DDR is majorly regulated by two protein families: the phosphatidylinositol 3-kinase-like protein kinase (PIKK) family  and the 16-member poly (ADP) ribose polymerase (PARP) family. Generally speaking, ATM, ATR, DNA-PK, and PARP mainly function as sensors for DNA damage. ATM is recruited by the MRN (MRE11/RAD50/NBS1) complex following recognition of DSBs , and ATMThe downstream effects of these repair processes involve activation of various substrates to elicit appropriate responses involved in cell fate determination. These downstream effectors include H2AX, CHK1, CHK2, and p53, among others. H2AX is phosphorylated to form γH2AX, which is one of the earliest events in DDR. γH2AX not only generates a signaling cascade to amplify the signal of DDR and recruits the DDR proteins but also regulates chromatin relaxation . CHK1 anNumerous studies have shown that Wnt signaling is highly intertwined with DDR . In thishttp://www.stanford.edu/group/nusselab/cgi-bin/wnt/target_genes. Based on these data, we have summarized the target genes closely related to DDR and briefly describe their roles in DDR.β-catenin is implicated in the regulation of DDR . ActivatAPC is a key effector of the canonical Wnt signaling pathway involved in downregulating the β-catenin level. Many previous studies have shown that the loss of APC function can cause chromosomal instability . Clarke Axin, a key scaffolding protein, is responsible for the formation of the β-catenin destruction complex. Stability of axin protein is regulated by the ubiquitin-proteasome system, and enhancing axin stabilization is a common method of inhibiting Wnt/β-catenin signaling. In DDR, axin interacts with PML to regulate p53-dependent apoptosis in response to DNA damage . Axin isFZD is the seven-pass transmembrane receptor of Wnt. FZD5 is a member of the FZD family. Zhao et al. revealed that FZD5 has been involved in triple-negative breast cancer (TNBC) cell G1/S transition and DNA damage repair partially dependent on Wnt7B . MoreoveGSK-3β is involved in multiple intracellular signaling pathways and is a component of the β-catenin destruction complex in Wnt signaling, which determines β-catenin stabilization. In DDR, GSK-3β can phosphorylate several DNA repair factors and affect their interaction with chromatin. For instance, through phosphorylating cyclin D1, CDC25A, and CRY2, GSK-3β can tune DNA repair and cell cycle . FurtherIn DDR, p53 can be activated in various ways. For example, ATM and ATR can phosphorylate p53 on Ser15 which is thought to inhibit interaction of p53 with the ubiquitin ligase, MDM2, leading to its dissociation from MDM2, thereby contributing to p53 stabilization . Likewiscyclin D1 and c-myc  or systemic (chemotherapy) treatments. Numerous kinds of drugs used for cancer chemotherapy, such as Adriamycin, etoposide, bleomycin, and cisplatin, are characterized as intense inducers of DNA damage and could effectively activate the intracellular DDR . All parTheoretically, targeting both DDR and Wnt signaling could serve as potential treatment strategies for cancer. Another common denominator of them is that DDR and Wnt signaling have been associated with therapeutic resistance . AlteratMost current anti-cancer chemotherapy approaches function by killing highly proliferating cells, which in many cancers are mostly non-CSCs. However, small CSC populations present in cancer have a higher repair mechanism and are also highly resistant to chemotherapy. In addition, radiotherapy and chemotherapy may trigger a series of cellular stress response mechanisms that enhance stem cell properties of non-CSCs, thereby improving their adaptation and survival. Therefore, compared with previous therapies, new combination therapies, which can kill both CSCs and non-CSCs while preventing the transition from non-CSCs to CSCs, require consideration. It would be possible to develop a therapeutic strategy which combines DDR-targeting drugs with Wnt-targeting drugs to increase sensitivity of cytotoxic drugs while contributing anti-CSC effects. Importantly, the connection points between the DDR and Wnt warrant further investigation, as drugs targeting these points are likely to inhibit both DDR and CSCs simultaneously.In the context of cancer, increased Wnt signaling is beneficial and reflected in enhancement of DDR, endowing cancer cells with increased ability to repair themselves during radiation or chemotherapy. The association between Wnt signaling and DDR in the post-carcinogenesis stage have been well studied, but the relationship between these two pathways during the process of carcinogenesis requires further investigation. There is a strong correlation between carcinogenesis and inadequate repair of DNA damage; however, whether Wnt signaling is involved in this process remains unknown. Future studies are required to investigate whether Wnt signaling can influence carcinogenesis via regulation of DDR.Although Wnt signaling and the DDR are closely related, the effects generated by different specific points of crosstalk are unknown. Identification of an appropriate regulator as a therapeutic target may be beneficial to cancer treatment. Compared with single-drug chemotherapy or radiotherapy, drug combination may achieve double efficacy with half the input. From another perspective, a triple therapy including DDR-targeting drugs and Wnt-targeting drugs has the potential to enhance the efficacy of radiotherapy and chemotherapy. Although our theory may be considered oversimplified, identification of crosstalk between the Wnt signaling pathway and DNA damage recognition has potential to provide novel insights into cancer therapy.


Primary cilia are antenna-like cell structures that protrude in a single copy from the surface of most vertebrate cell types to detect extracellular cues that regulate embryonic patterning, organogenesis, and adult tissue/organ homeostasis. The capacity of primary cilia to detect and transduce signaling information into cellular processes relies on their unique complement of receptors, ion channels, and associated signal transduction modules, e.g., G protein-coupled receptor (GPCR), receptor tyrosine kinase (RTK), Hedgehog, Wnt, transforming growth factor-beta (TGFB)/bone morphogenetic protein (BMP), and extracellular matrix (ECM) signaling . All cilvia distal appendage proteins (DAPs)  in ciliogenesis during embryonic fore- and hindlimb development in novel Sclt1 mutant mice. Sclt1 regulates ciliogenesis in developing hindlimb mesenchymal cells by facilitating recruitment of Ttbk2 and removal of Cp110 from the mother centriole, which is associated with a response to Sonic hedgehog signaling. The authors provide the tissue-specific DAP assembly programs during embryonic limb morphogenesis, suggesting multiple pathogenic functions of ciliary genes in pleiotropic phenotypes of ciliopathies.Multiple protein complexes are required for assembly and sensory properties of primary cilia. A modified mother centriole called the basal body anchors the cilium to the cell membrane in part s (DAPs) . RemovalZheng et al. overviews the structure and cellular functions of IFT172 in ciliary assembly and maintenance as well as Sonic hedgehog signaling activation. Hedgehog signaling is one of the best-characterized cilia-based signaling systems in vertebrates and one of the critical morphogens regulating tissue patterning and morphogenesis during embryonic development , Mainzer-Saldino syndrome (MZSDS) and BBS, and remark on the importance of further investigation into the functional and pathogenic mechanisms of IFT172 in ciliopathies. In line with the function of the BBSome in ciliary receptor trafficking, Stubbs et al. analyze the localization of GPCRs (somatostatin receptor 3 (Sstr3), melanin-concentrating hormone receptor 1 (Mchr1), dopamine receptor 1 (D1), Gpr161, and Gpr19) and their downstream effectors (type 3 adenylyl cyclase and β-arrestin) in different brain regions of a novel Bbs1 knockout mouse. The authors observe intriguing brain-region-specific differences in ciliary localization of the above GPCR pathways’ components and demonstrate that BBSome may control ciliary entry/retention of Sstr3 and Mchr1 and exit of D1, Gpr161, and Gpr19, thus revealing additional complexity in protein- and cell-type-specific mechanisms guiding ciliary localization of signaling proteins in the developing brain.Intraflagellar transport (IFT) is a bidirectional transport system that tracks along the polarized microtubules of the axoneme and mediates ciliary assembly, maintenance, and signaling through the transport of ciliary cargo proteins into or out of the organelle . Bidirecelopment  as well elopment . Zheng eXu and Tang overview the role of cholesterol in regulating multiple aspects of Sonic hedgehog signaling, including posttranslational modification and transportation of proteins in this pathway. The authors further review the reciprocal effects of Sonic hedgehog signaling in cholesterol metabolism and homeostasis and discuss the birth defects, e.g., holoprosencephaly, associated with mutations of Sonic hedgehog genes.Pittman and Solecki focuses on the pivotal role of primary cilia in balancing the morphogen  sensing and integrin-ECM interaction during cerebellar granule neuron (CGN) differentiation. Specifically, the authors discuss how different ECM components influence cilia maintenance in a niche-specific manner during CGN differentiation and bring into focus the intriguing cooperative roles of integrins and cilia in sensing the mechanical forces in the developing cerebellum.Emerging evidence points to a critical function of primary cilia is detecting morphogenic cues in combination with biomechanical forces, such as through interaction with the extracellular matrix (ECM) to control neuronal differentiation in the developing and adult brain. The minireview by In summary, the articles in this Research Topic enhance the understanding of the ciliary structural components and signaling pathways during development, provide additional insight on the pathogenesis of ciliopathies and birth defects, and bring forth insightful ideas for future investigations.


Duplication of the  The as (CMT1) . A high-PMP22 gene mutation is most frequently confirmed in CMT disease, greater than 100 gene mutations are known to cause CMT phenotypes which may be inherited in an autosomal dominant, autosomal recessive, or X-linked manner [MPZ gene and produced by Schwann cells, it is important for myelin compaction [MPZ gene mutations are being increasingly recognized as causes of certain forms of hereditary peripheral neuropathy including CMT disease and early-onset Dejerine-Sottas disease [MPZ gene account for 10-12% of all dominant demyelinating CMT type 1 cases [PMP22 gene mutations, there have been several recent publications on the genetic spectrum of CMT disease associated with the MPZ gene mutations [While the d manner . A type d manner ,9. Encodmpaction -10. The mpaction . MPZ gen disease ,9. Additutations -10. In this report, we describe the clinical symptoms of two family members diagnosed with CMT2 disease with the MPZ genetic variant, one at the onset and the other in the late stage, both of whom underwent electrodiagnostic (EDX) and ultrasound (US) studies. The presenting symptoms, clinical and EDX findings, and US features are presented. The physiological role of the MPZ genetic variant and how missense mutations affects its function are discussed. Two family members, a mother in the late stage and her son in the early stage of disease, underwent a focused neurological examination followed by EDX and US evaluation of peripheral nerves. The CMT neuropathy score (CMTNS) was estimated . The EDXPatient 1 (mother)Clinical FindingsA 71-year-old female started experiencing numbness in her feet at age 39 and later began to trip and fall at age 50. When she was initially evaluated in our facility, she walked with an ankle foot orthosis (AFO) brace and a walker to help with ambulation and to avoid falls. Clinical findings are summarized in Table A significant weakness of the dorsiflexors and plantar flexors of the feet was noted bilaterally (dorsiflexor weakness was more pronounced) with loss of the ankle reflexes. Decreased pinprick and light touch sensations up to the midcalf and absent vibration sense at the ankle were observed. Position sense was erratic at the big toes. There was also the weakness of intrinsic hand muscles and decreased pain and light touch sensations over the digits and the hands up to the wrist. The patient was evaluated six years later at which time she had experienced significant progression of muscle weakness and needed a wheelchair. The knee and ankle reflexes were absent. Pinprick and light touch were absent up to the knees. There was an absence of both position sense in the big toes as well as vibration sense at the ankles and knees. The upper extremities showed significant weakness and wasting of the intrinsic hand muscles Figure , 2B, andDuring the six years following the initial encounter, there was a significant worsening in muscle strength and more atrophy. The thigh muscles were normal at the first visit but showed weakness and atrophy during the second visit. The biceps and triceps reflexes were intact  at the initial visit but were absent at the subsequent visit. The level of sensory loss also progressed steadily to involve the more proximal areas of the upper and lower limbs Table . EDX StudiesThe nerve conduction and electromyography (EMG) findings are summarized in Table US Study2 at the wrist  and 7 mm2 at the mid-forearm . The ulnar nerve was also studied at the elbow, and the CSA was 9 mm2 .The cross-sectional area (CSA) of the median nerve was measured at the wrist and mid-forearm Figure , 3B. ThePatient 2 (son)Clinical FindingsA 48-year-old male reported a history of numbness and intermittent sharp pain in the feet bilaterally. He denied symptoms in the upper extremities and did not experience muscle weakness or a tendency for falls. Neurological examination showed high-arched feet. Pinprick sensation was diminished over the plantar and dorsal aspects of both feet. Position, vibration, and light touch sensations were normal. The ankle reflexes were absent bilaterally, and the knee reflexes were normal. Gait was also normal.EDX StudiesThe NCV/EMG studies showed slowing of the motor conduction of the median nerves, although were >38 m/s. The fibular nerves revealed slowing of motor conduction. No SNAPs could be recorded over the superficial fibular or superficial radial nerves; the median and ulnar nerve SNAPs showed a low amplitude. US Study2 at the wrist  and 8 mm2 at the mid-forearm . The ulnar nerve was also studied at the elbow, and the CSA was 10 mm2 .The CSA of the median nerve was measured at the wrist and mid-forearm. The CSA of the median nerve was 11 mmFamily HistoryNo other family members have been diagnosed with CMT disease. Figure Diagnosis of CMT Disease and Genetic TestingBoth patients were diagnosed with CMT2 disease based on clinical and EDX findings, with the latter test demonstrating the median nerve motor conduction velocity >38 m/s. Genetic studies confirmed a heterozygous identical variant of MPZ in Exon 2.c109G>A p.Glu37Lys) for both patients 1 and 2. Inherited in an autosomal dominant fashion, this single-nucleotide variant has a cytogenetic location on chromosome 1q23.3 Lys for b. The varMPZ gene mutations have been identified as the cause of inherited peripheral neuropathy, exhibiting a wide range of phenotypes with varying severity of clinical symptoms [MPZ gene mutations into early-onset, childhood/adolescent-onset, and late-onset phenotypes [More than 300 symptoms ,9,13. Thsymptoms ,14. Sanmsymptoms . These aenotypes .MPZ gene mutations were uncovered, including four known and two novel. EDX studies revealed a chronic progressive sensorimotor demyelinating polyneuropathy. These authors described that their patients with MPZ gene mutations had relatively mild clinical phenotypes [MPZ gene variants and 21 patients with 17 novel MPZ gene variants [p.Ser111Tyr that occurred at or near the same codon. These authors presumed that the confirmed novel variants likely induced a pathogenic phenotype, especially in these missense variants [In Chen and colleagues’ study of genetic and clinical features in six patients with CMT1B from unrelated Chinese families, all patients initially complained of weakness in the lower extremities . Six MPZenotypes . Tanigucvariants . A singlvariants . The MPZvariants . This paTwo categories of MPZ mutations are responsible for a demyelinating phenotype: (1) nonsense and frameshift mutations that delete large segments of MPZ leading to loss of structure and function and (2) missense mutations that disturb the structure and function of MPZ, cause intracellular folding problems with MPZ, or mislocalize MPZ . MissensMPZ gene mutation in CMT disease in early and late stages. Patient 1 started having symptoms at age 39 and demonstrated more advanced disease at her initial visit with upper extremity involvement. Patient 2 experienced sensory symptoms of the lower extremities at age 47. Both patients had sensory abnormalities of the distal lower extremities and absent ankle reflexes. The mother had significant weakness in the feet and intrinsic hand muscles. The MNCV of the median nerves was slowed in both patients, and SNAPs were absent over the superficial radial and superficial fibular nerves. Both patients’ findings were consistent with CMT2 disease with axonal involvement. The family described in this case report provided a unique opportunity to study the phenotypical features of the p.Glu37Lys MPZ gene mutations and the resulting phenotypical features is crucial for understanding the pathogenetic mechanism. While demyelinating neuropathies can be easily explained based on the role of MPZ in myelin compaction, the mechanism of axonal neuropathies is not fully understood. One theory is that MPZ-related axonal neuropathies may be due to the disruption of myelin-axon interactions [The study of ractions . The occractions . Understractions . The assractions .To our knowledge, only one previous patient has been reported with the newly described MPZ variant p.Glu37Lys in CMT disease. Our two patients with this same MPZ variant offer valuable insight into the progression of the disease from the early to the late stages of CMT disease. We also illustrate the clinical, EDX, and US features of the newly described mutation of MPZ in CMT disease.


Theoretically, whether a more loosely regulated labour market inhibits or fosters fertility in a society is ambiguous. Empirically, the few studies analysing the relationship between the strictness of employment protection legislation—the norms and procedures regulating labour markets’ hiring and firing processes—and fertility have found mixed evidence. This paper reconciles the ambivalent conclusions of previous studies by analysing the impact of employment protection legislation and labour market dualism on total fertility across 19 European countries between 1990 and 2019. Our results indicate that an increase in employment protection for regular workers positively affects total fertility. Nonetheless, an increasing gap between the regulation of regular and temporary employment—that is, labour market dualism—negatively impacts total fertility. These effects, of small-to-moderate intensity, are relatively homogeneous across age groups and geographical areas and are especially pronounced among the lower educated. We conclude that labour market dualism, rather than a “rigid” employment protection legislation, discourages fertility. Since the beginning of the 1990s, the relatively strict employment protection legislation (EPL)—the norms and procedures regulating labour markets’ hiring and firing processes OECD, —of EuropThe literature on the effect of an individual’s labour market situation on family formation has often focused on single episodes of unemployment or temporary employment over one’s life course, by means of event history analyses modelling the effects of labour market transitions, for example, job losses or shifts from fixed-term to permanent contracts. A consistent stream of studies has shown that flexible and temporary work contracts delay the transition to adulthood and lead to fertility postponement and decline  EPL guarantees strong employment protection for regular workers, while a flexible  EPL allows more unstable jobs.EPL includes all norms regulating labour markets’ hiring and dismissing processes; for example, EPL includes conditions for using temporary contracts, redundancy procedures, mandated prenotification periods and severance payments, special requirements for collective dismissals, and so forth. It refers to all types of employment protection measures, whether grounded primarily in legislation, court rulings, collectively bargained conditions of employment, or customary practice OECD, . The dega deregulated labour market may hinder fertility rates.By influencing individuals’ job stability, EPL has the potential to influence fertility  existing studies on the link between EPL and fertility ignore that the EPL reforms of the last 3 decades mostly affected employment patterns by creating labour market dualism through marginal and/or targeted provisions that only apply to new jobs. Such reforms mostly penalize labour market entrants, and especially the youth, women and low-skilled workers with intermittent employment spells  fosters higher fertility rates.By contrast,Increasing labour market dualism (EPL-gap) leads to lower fertility rates.Group-specific differences—for example, age and education—in the impact of EPL on fertility have seldom been considered in previous research. Nevertheless, research on the impact of EPL on employment patterns has found that the degree of rigidity/flexibility of EPL has different effects across subgroups of workers , while the negative effect of an increase in the EPL-gap will be stronger for the lower educated (Hypothesis 2a).In particular, we expect that The effects of labour market reforms may also vary across institutional contexts Balz, . For inswe account for possible heterogeneity in the impact of EPL on fertility across different country-areas.Considering this substantial variation in welfare regimes and labour market contexts in Europe, it is difficult to advance specific hypotheses; however, in this study, In Europe, most employment protection norms in the modern form were developed through legislation, collective agreements, and court rulings between the 1960s and 1980s. The process of increasing employment protection through the regulation of hiring and firing dynamics reached relatively regulatory stability during the 1980s OECD, . Since tA tendency towards the deregulation of regular contracts began at the end of the first decade of the 2000s, following the onset of the financial crisis OECD, . The actAnother wave of deregulation reforms occurred in the most recent period 2014–2019) in an attempt to reduce labour market dualism 3Our dependent variable is the countries’ total fertility rate (TFR) provided by OECD. To test for heterogeneity across age and educational groups, we additionally used age- and education-specific fertility rates as dependent variables. Age-specific fertility rates are provided by Eurostat and are available for all countries and years except for France and Germany, where they are available beginning in 1998 and 2000, respectively. Education-specific fertility rates have been calculated from Eurostat data. The rates are based on the number of live births by the mother’s level of education (15–39 years old) divided by the total number of women by the level of education (15–39 years old) for each country and year. Information is only available from 2007 to 2019,The main explanatory variables are derived from the OECD employment protection indexes for regular and temporary workers. The OECD indexes are compiled from 21 items covering different aspects of employment protection regulations in a country, as they were in force on 1 January of each year. Information is collected from detailed questionnaires completed by local experts, government authorities, and the OECD Secretariat, integrated with national and international secondary sources . Then, it is converted into a score measured on a 0–6 scale, with higher values representing stricter regulation OECD, , 2013. TThe OECD EPL indexes are the best available comparative indicators of employment protection legislation. The OECD puts extensive efforts into making these indicators more and more valid and reliable OECD, , 2019, aFigure We empirically estimated the impact of EPL on fertility with a fixed-effect (FE) estimator, that is, by analysing within-country variations. Formally, our model can be described as follows:c and t in the subscripts stand for country and time). All variables are country de-meaned (as indicated by the tildes) to capture within-country variation. The element One of the problems with the current literature on EPL effects is that most of the evidence is based on cross-country time-series data, which is generally affected by endogeneity and measurement problems .In Eq. , \documeSeveral robustness checks are provided in Sect. Model 1 in Table p value 0.000). Thus, in Model 3, we return to a FE estimation, and we add our controls for family polices, i.e. the number of weeks of paid maternity leave, and public spending on the family. Accounting for these two variables, the effects of EPL-r and EPL-gap remain statistically significant and of a similar magnitude as in Model 1. Finally, in Model 4 we also account for labour market characteristics, i.e. the unemployment rate and women’s employment rate. Adding these two variables to our model, the effect of EPL-r shrinks and loses statistical significance, while the effect of EPL-gap remains stable. Indeed, unemployment and women’s employment may also depend on EPL. The effect of EPL-r, therefore, could be captured by changes in unemployment and women’s employment.For comparison, Model 2 displays the results of the same model obtained with a random-effect (RE) estimator. Even with this specification, that also includes the between-country variation, a wider gap in the protection of regular and temporary workers is associated with lower fertility rates, while the effect of EPL-r is virtually null. Nevertheless, due to the limitations of the EPL indexes, employing between-country variation is likely to produce biased results due to endogeneity and measurement problems. Moreover, the Hausman test confirmed that the hypothesis that the country-level effects are adequately modelled by a random-effect model is resoundingly rejected ; its largest effect is found in the 30–34 age group.Next, we assessed the fertility effects of changes in EPL-r and EPL-gap for lower-, middle- and highly educated women. Results are shown in Table Finally, the predicted TFRs for each group of countries at different levels of EPL-r and EPL-gap, based on Eq. , are disOur main results hold after a series of robustness checks. First, we tested the model in Eq.  substituThen, in order to test to what extent the relationship between EPL and fertility is driven by few countries where variations in EPL are particularly marked, we run our models removing countries such as Portugal and Greece. Our results (available upon request) were robust also to this test.Finally, some of our control variables may be influenced by the EPL (i.e. the unemployment rate and women’s employment rate). Thus, measuring them simultaneously may conceal some of the effects of EPL. Moreover, responses of fertility rates to changing institutional and economic factors might be delayed. Therefore, we ran two additional models to account for the ordering of effects and possible delayed fertility responses, which can be found in the appendix Table . The estFertility decline is a matter of major concern on the European agenda, as most EU countries have long been marked by low fertility rates, with negative implications for population ageing and welfare systems. After a rebound in fertility rates in the early 2000s, in the last decade, fertility has again dropped in most European countries. Understanding whether and how labour market flexibilization reforms influence fertility trends is, therefore, of remarkable importance.This paper evaluates the fertility consequences of the several waves of labour market deregulation reforms implemented in Europe starting from the beginning of the 1990s. We found that, overall, a more regulated and protected labour market is beneficial for fertility while the gap between the regulation of regular and temporary contracts, that is, labour market dualism, hinders fertility plans.Increasing job protection leads to higher fertility for all age groups, and especially for the youngest ones (aged below 30). In the same fashion, labour market dualism is detrimental to the fertility of all age groups, except for the youngest (aged below 24) for which the effect is virtually null. Nevertheless, at very young ages, fertility rates are very low in European countries, and their determinants are likely to be different . Thus, more research is needed to evaluate differences in the effects of labour market deregulation reforms on the fertility of different educational groups. Third, although we accounted for interactions between EPL and country-areas, further research is needed to delve into the analysis of country-specific differences concerning the relationship between EPL and fertility. Finally, despite the literature reports that changes in EPL affect differently women’s and men’s employment chances, due to our macro-level approach we are not able to disentangle the effects of these gendered processes on aggregate fertility.Our paper has several limitations. First, our main explanatory variables, the OECD EPL indexes, heavily rely on subjective assessments. For this reason, despite their extensive use in scientific research and policy evaluation, they have been widely criticized regulation on fertility over the last 30 years, our study reconciles the ambiguous conclusions of existing studies on the impact of employment protection legislation on fertility in Europe. Indeed, it shows that increasing the gap between the regulations of regular and temporary employment through marginal EPL reforms has a negative impact on fertility, especially among low-educated women. On the contrary, increasing employment protection per se has positive effects on fertility, irrespective of age and education. Even if effect sizes are often of small-to-moderate intensity, our results highlight the detrimental consequences of increasing labour market dualism on the reproductive behaviours of Europeans. Policymakers should therefore consider that increasing labour market deregulation and dualism may negatively impact fertility rates.


The survival rates for cancer patients have been steadily improving in recent years due to the improved efficacy of contemporary oncological care, including radiotherapy and chemotherapy. Modern technology makes it feasible to maintain fertility in cancer patients, and this practice needs to be included in oncological care. In many instances, it is impossible to avoid the harm that cancer treatments can cause to a patient's fertility; hence, research in fertility preservation techniques is being conducted to allow cancer patients to have future children biologically related to them. The development of fertility preservation approaches has grown in importance in the field of research over the past few years to increase patient's quality of life and survival. Oncologists must be aware of circumstances in which cancer patients' fertility will be impacted by their therapy and the avenues open for procedures like cryopreservation of the gametes or embryos. When cancer therapy is scheduled, all patients should receive prompt and thorough information on the fertility-related side effects of treatment and the prospects for fertility preservation. The article analyzes the literature, enlisting the factors that contribute to cancer and their effects on fertility, followed by a list of available and newly developed strategies for maintaining fertility in patients. The efficiency of the various fertility preservation techniques following cancer therapy is also discussed. Treatment for oncological disorders may affect fertility in patients according to their age at the beginning of the treatment, its duration, severity, and type . AlthougImpact of cancer therapy on fertilityThe cornerstone methods for treating cancer are still chemotherapy and radiotherapy . Given tFemalesIn young female patients, ovarian toxicity is a severe consequence of cancer treatment . All femMalesMale cancer patients may experience reduced sperm transport due to poor sperm generation or reduction in the population of spermatogonial stem cells . RadiatiFurthermore, dose fractionation appeared to impair sperm production rather than improve testicular function . Leydig Methodology A thorough literature search was conducted to discover relevant fertility preservation studies in cancer patients. The search was undertaken in English utilizing electronic databases such as PubMed, MEDLINE, Embase, and Google Scholar. The search terms were chosen to highlight cancer and fertility management and their impact on people at various phases of life. The subject terms chosen were “fertility preservation”, “cancer", "female", "male", and "oncofertility”. Peer-reviewed articles published in English for the secure recovery of fertility in cancer patients and the various known choices for preserving fertility in individuals undergoing cancer therapy were included in this article. Exclusion criteria included research not directly connected to fertility preservation, non-human studies, and studies that did not have full-text access. The final articles for the review were chosen after additional screening of full-text articles for potentially pertinent research. The inclusion criteria were satisfied by 40 papers included in the final review. The study selection procedure is outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram, shown in Figure Fertility preservation techniques for female patientsOocyte and Embryo CryopreservationFor adult females, retrieval of oocytes for freezing, in vitro fertilization (IVF) of the recovered oocytes, and the subsequent cryopreservation of the fertilized oocytes are the standard procedures . The womOocyte cryopreservation is a viable alternative if a sperm donor isn't available or where embryo cryopreservation isn't permitted by legislation ,17. The Cryopreservation of Ovarian TissueOvarian tissue cryopreservation (OTC) entails freezing the ovarian tissue, containing primordial follicles . It invoOvarian TranspositionOvarian transposition, also known as oophoropexy, is a technique that removes the ovaries from the radiation field by detaching one or both ovaries and fallopian tubes from the uterus and securing it to the abdominal wall away from where the radiation will be directed . OvariesOther ConsiderationsThe practice of preserving fertility has been expanding quickly, with various regimen strategies for chemotherapy-induced infertility still in the preliminary stage, awaiting clinical trial findings. Despite being less researched, various approaches have shown promise in preliminary research .Cancer patients may benefit from xenotransplantation because it does not involve autotransplantation, which carries the risk of reintroducing cancer cells . NonetheOvarian tissue cryopreserved from prepubescent patients and POF patients have immature primordial follicles that must be stimulated to grow, which can be induced in vivo by disrupting the Hippo signaling pathway or in vitro before autotransplantation ,28.Counseling of individuals who have breast cancer regarding the choices for preservation of fertility should go beyond the mere discussion of the effects of chemotherapy on the ovarian reserve count. The patient's age, required number of offspring, queries regarding the kind of tumor, the existing BRCA mutation, sensitivity to hormones, and concerns regarding the chance of becoming pregnant following breast cancer therapy can all differ significantly between patients ,29. PatiThe long-held notion that a dormant group of primordial follicles limited a woman's reproducing capacity was questioned further . The abiFertility preservation techniques for male patients Sperm CryopreservationSperm cryopreservation remains the clear alternative for males who can produce a sperm sample. It is mainly achieved by ejaculation of the semen. Additionally, it can be accomplished through testicular biopsy, testicular sperm extraction, and epididymal sperm aspiration, which can be done percutaneously or microsurgically ,10. In cCryopreservation of Testicular Tissue Testicular tissue cryopreservation is still in its early stages but appears promising for fertility preservation in prepubertal children and adolescents . SpermatCurrent gaps in the information regarding preservation of fertility Although research and studies have shown that patients who have battled cancer are prone to non-specific symptoms like stress, anxiety, and a poor quality of life, several cancer patients in their reproductive years fail to obtain enough information about fertility preservation or a recommendation to consult a reproductive specialist ,38. PsycNowadays, many men and women are experiencing disease-free conditions in oncological healthcare. With improved chances of recovery and sustained survival, there is a need to address various options to preserve the fertility of the patients at the time of diagnosis and survivorship. The best procedure should be chosen among those available depending on the patient's characteristics: male, female, prepubertal, or postpubertal. Cryopreservation of sperm and embryos is considered standard practice and is commonly done. Other existing techniques should be treated as experimental and carried out in facilities with the required knowledge. The article focuses on addressing fertility preservation techniques for patients battling cancer and providing them with help and guidance to deal with their fertility issues. Future studies should focus on the methods to help people and healthcare professionals make decisions and prompt referrals to improve the success of fertility preservation.


As this bystander mechanism is triggered conceivably by the transmigration of HTLV-1-infected CD4+ T cells to the spinal cord, heightened transmigrating activity of HTLV-1-infected CD4+ T cells to the spinal cord might play a crucial role as the first responder in the development of HAM/TSP. This review evaluated the functions of HTLV-1-infected CD4+ T cells in HAM/TSP patients as the prerequisite for the acquisition of the activity such as adhesion molecule expression changes, small GTPases activation, and expression of mediators involved in basement membrane disruption. The findings suggest that HTLV-1-infected CD4+ T cells in HAM/TSP patients have enough potential to facilitate transmigration into the tissues. Future HAM/TSP research should clarify the molecular mechanisms leading to the establishment of HTLV-1-infected CD4+ T cells as the first responder in HAM/TSP patients. In addition, a regimen with an inhibitory activity against the transmigration of HTLV-1-infected CD4+ T cells into the spinal cord might be recommended as one of the therapeutic strategies against HAM/TSP patients.Slowly progressive spastic paraparesis with bladder dysfunction, the main clinical feature of human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), is induced by chronic inflammation in the spinal cord, mainly the lower thoracic cord. A long-standing bystander mechanism, such as the destruction of surrounding tissues by inflammatory cytokines, etc., induced under the interaction between infiltrated HTLV-1-infected CD4 In addition to this situation, a positive feedback loop, which is formed by chemokine CXCL10 induced from astrocytes via stimulation by IFN-γ produced by infiltrated HTLV-1-infected Th1-like CD4+ T cells, might be involved in the maintenance and promotion of chronic myelitis [+ cells, which are attracted by CXCL10, provide the additive effect for a positive feedback loop (Human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic progressive myelopathy characterized by bilateral pyramidal tract involvement with sphincteric disturbances . Althougpatients . In addipatients . Thus, apatients . The examyelitis ,12,13  and vascular cell adhesion molecule-1 (VCAM-1), is upregulated in HTLV-1-infected cells .x antigen (sLex) is a ligand for both E- and P-selectin [x (sLex+ cell) might have the potential to transmigrate into tissues. We previously compared the frequency of sLex+ cells together with IFN-γ production in peripheral blood CD4+ T cells between 8 HAM/TSP patients and 14 controls, including four anti-HTLV-1-seropositive carriers [x+ cells in peripheral blood CD4+ T cells of HAM/TSP patients was significantly higher than in controls. In addition, the activity of IFN-γ production in the sLex+ cell population in the peripheral blood CD4+ T cells of HAM/TSP patients had significantly increased compared to controls. Futhermore, when we compared HTLV-1 proviral load between sLex+ and sLex− cell populations, HTLV-1 proviral load in the sLex+ cell population was two- to eight-fold higher than the sLex− cell population. Thus, in the peripheral blood CD4+ T cells of HAM/TSP patients, the frequency of sLex+ cells  increased, and the HTLV-I provirus was concentrated in the sLex+ cell population. These findings suggested that HTLV-1-infected Th1 cells having the potential to cause the trigger for transmigration to the spinal cords are increased in the peripheral blood CD4+ T cells of HAM/TSP patients.In the process leading to the transmigration of T cells into the tissues, the rolling process of T cells on vascular endothelial cells (ECs) functions as the first step . Selectiselectin . Therefocarriers . As showFollowing the rolling process on ECs, the firm adhesion of T cells by the interaction between integrins and their ligands plays a crucial role as the preliminary step for transmigration of T cells into the tissue ,28.+ T cells, but not CD8+ T cells, with heightened lymphocyte function antigen-1 (LFA-1) expression belonging to integrin family [We previously reported significantly increased adherence of peripheral blood T cells to ECs in HAM/TSP patients  as eviden family ,31. Romen family . This sun family . This BBn family  or proinn family  followinn family . In thisn family ,37. Recen family .On the other hand, the abnormalities of very late antigen-4 (VLA-4) (a member of the integrin family and a ligand of vascular cell adhesion molecule-1(VCAM-1), expressed on T cells) are also reported. Immunopathological analysis of spinal cord lesions in HAM/TSP patients revealed that infiltrating mononuclear cells expressed VLA-4 concomitantly with highly expressed VCAM-1 on the vascular endothelium were detectable on perivascular infiltrating cells and endothelium in active chronic lesions . Thus, tThus, the upregulation of cell adhesion molecule expression on HTLV-1-infected cells of HAM/TSP patients might have enough potential to facilitate the transmigration of HTLV-1-infected cells through ECs. However, although the expressions or the activities of LFA-1, LFA-3, ICAM-1, VCAM-1, and ALCAM, etc., are associated with HTLV-1 tax or HBZ activity ,35,41, tSmall GTPases function as the propulsion for the transmigration of the cells through ECs. That is, small GTPase activation can induce the upregulation of transmigration activity of the cells into tissues through the rearrangement of the cytoskeleton involved in the adhesion and migration of cells . The fin+ T cells with heightened LFA-1 expression in the peripheral blood T cells of HAM/TSP patients as mentioned above [+ T cells of HAM/TSP patients. Subsequently, the upregulation of integrin/ligand signaling induces the activation of small GTPases, which are the downstream targets, followed by the rearrangement of cytoskeletal components [We previously reported the significantly increased adherence to ECs and subsequent transmigration through ECs of activated CD4ed above ,31, suggmponents ,46. Thermponents . As a remponents  with themponents ,50. TherIntegrins can also conduct inside-out signaling, and this function also might be involved in transmigrating activity into the tissues of HTLV-1-infected cells of HAM/TSP patients. Rap1, a small GTPase that functions in a complex with adaptor molecules, such as RAPL, talin1, and kindlin-3, facilitates the inside-out signaling for integrin signaling, leading to increased adhesion to integrin ligands ,52. ActiThus, activation of small GTPases through both outside-in signaling from integrin and inside-out signaling for integrin in HTLV-1-infected cells of HAM/TSP patients can induce heightened transmigrating activity into the tissues, and these activities might function as one of the first responder roles in the development of HAM/TSP  Figure .+ T cells of HAM/TSP patients was significantly inhibited by selective MMP inhibitor [When considering the transmigration of T cells into the tissues after passing through the endothelium barrier, the extracellular matrix, including the vascular basement membrane, functions as the next barrier. Although collagens, gelatine, fibronectin, and laminin are the main components of the vascular basement membrane, matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9, can cleave these components followed by the disruption of the basement membrane of the endothelium . Indeed,nhibitor . Recentlnhibitor .Recent proteomic analysis of CSF revealed an increased level of soluble VCAM-1 (sVCAM-1) in HAM/TSP patients ,61. It iWhen considering the importance of MMP expression in the contact to cell adhesion molecules, we previously demonstrated that VCAM-1-mediated MMP-2 induction was up-regulated in T cells of HAM/TSP patients . This fi+ T cells of HAM/TSP patients through the basement membrane, we previously investigated the transmigration of peripheral blood CD4+ T cells of HAM/TSP patients through the reconstituted basement membrane (RBM) using Transwell inserts, which were polyvinylpyrrolidone-free polycarbonate filters pre-coated with laminin on the lower surface and RBM (Matrigel) on the upper surface, respectively [+ T cells of HAM/TSP patients through RBM was significantly higher than that of either HTLV-1-seropositive carriers or HTLV-1-seronegative controls. Subsequently, we found that HTLV-1 proviral load in transmigrated CD4+ T cells from HAM/TSP patients was significantly higher than in non-transmigrated CD4+ T cells. By contrast, no significant difference was found in HTLV-1 proviral load in transmigrated and non-transmigrated CD4+ T cells from HTLV-1-seropositive carriers. These results indicated that peripheral blood CD4+ T cells of HAM/TSP patients, particularly HTLV-1-infected CD4+ T cells, have heightened transmigrating activity based on the induction of RBM disruption, suggesting that the character of the heightened transmigrating activity of HTLV-1-infected CD4+ T cells through the vascular basement membrane acquires the ability to accumulate in the tissues and is consistent with the findings that HTLV-1 provirus accumulates in CSF in HAM/TSP patients compared to HTLV-1 asymptomatic carriers as earlier described [+ T cells of HAM/TSP patients, the increased activity of aminopeptidase-N (APN), which is one of cell surface proteases as same as MMPs [To evaluate the transmigrating activity of peripheral blood CD4ectively . The resescribed ,18. As t as MMPs  was obse+ T cells in HAM/TSP patients have sufficient activity to induce mediators to disrupt the vascular basement membrane for tissue transmigration.Thus, these findings strongly suggest that HTLV-1-infected CD4+ T cells in HAM/TSP patients into tissues, as mentioned above, is summarized in Finally, the series of molecular events involved in the heightened transmigration activity of HTLV-1-infected CD4Several inflammatory diseases, such as Sjögren’s syndrome , myositiWe previously reported interstitial cystitis and persistent prostatitis in HAM/TSP patients with concomitant appearance of anti-HTLV-1 antibody in urine  and HAM/+CD4+ cells, was observed in the labial salivary glands of all examined HAM/TSP patients, suggesting that CD4+ T cells of HAM/TSP patients have transmigrating activity into the salivary glands even if its occurrence is not severe enough to induce the pathological changes that cause Sjögren syndrome, although the determination of these CD4+ T cells as HTLV-1-infected cells was not investigated. In addition, we analyzed the existence of ectopic germinal centers (GCs), one of the characteristic pathological features of Sjögren syndrome [+ T cell infiltration into the salivary glands.We previously reported that Sjögren syndrome occurs very frequently in HAM/TSP patients . In thissyndrome , in the syndrome , suggestOverall, the HTLV-1-infected T cells in HAM/TSP patients might also have the potential to induce the trigger for the development of systemic inflammatory status as the first responder or maintain its status by the heightened transmigrating activity into the tissues.The ideal treatment for HAM/TSP patients is the complete elimination of HTLV-1-infected cells. However, the therapeutic strategy against HAM/TSP is yet to be established. Therefore, a regimen with an inhibitory activity against the transmigration of HTLV-1-infected cells as the first responder into the spinal cord might be recommended as one of the therapeutic strategies. The main regions in which pathological changes occur in HAM/TSP are in the lower thoracic spinal cord . These rPentosan polysulfate sodium (PPS), which was developed as a heparin-like agent and has been used in Europe for thrombosis prophylaxis and treatment of phlebitis, is a semisynthetic drug manufactured from European beech-wood hemicellulose by sulfate esterification . TherefoBased on the efficacy of heparin treatment, as demonstrated in our previous clinical trial against HAM/TSP patients , we test+ T cells might play a crucial role as the first responder. Therefore, the activities of HTLV-1-infected CD4+ T cells in HAM/TSP patients were evaluated based on the transmigration activity into the tissues. Consequently, it was demonstrated that HTLV-1-infected CD4+ T cells in HAM/TSP were supposed to have enough heightened transmigrating activity into the tissues based on the activation of integrin signaling followed by small GTPase activation with the up-regulated expression of MMPs. This activity appears sufficient to allow HTLV-1-infected CD4+ T cells to function as the first responders in the development of HAM/TSP. In addition, the HTLV-1-infected CD4+ T cells in HAM/TSP patients might also have the potential to induce the trigger for the development of another systemic inflammatory status, including Sjögren’s syndrome, myositis, and uveitis, etc., which occasionally occur in conjunction with HAM/TSP, as the first responder.Considering the mechanism of chronic inflammation induced in the spinal cord of HAM/TSP patients, HTLV-1-infected CD4+ T cells as the first responder in HAM/TSP patients. At this point, the acquisition of heightened transmigrating activity of HTLV-1-infected CD4+ T cells into the tissues among HTLV-1-infected individuals seems to be the key event leading to the development of HAM/TSP. However, it is still unclear how the change of signal molecules supporting the expression of the heightened transmigrating activity of HTLV-1-infected CD4+ T cells in HAM/TSP patients demonstrated in this review are induced among HTLV-1-infected individuals. For example, is it based on the existing signal molecules or other novel signal molecules, or is it simply based on the increase of HTLV-1-infected Th1 cells?Although the exact reasons why HTLV-1 induces HAM/TSP in a very small population of HTLV-1-infected individuals are still unsolved, a very important task in future HAM/TSP research is to clarify the molecular mechanisms leading to the establishment of HTLV-1-infected CD4In small GTPase activation, although the finding that HTLV-1 tax regulates cell adhesion and migration by the interaction with Cdc42, Rac, and Rho involved in the outside-in signaling from integrin signaling was previously demonstrated , the int+ T cells as the first responder in HAM/TSP patients. When considering the therapeutic strategy for HAM/TSP patients, the regimen, which has an inhibitory activity on the transmigration of HTLV-1-infected cells into the spinal cord, might be recommended as one of the therapeutic strategies. At this point, integrin-targeting drugs, such as natalizumab or vedolizumab, which function by the inhibition of ligand to integrins and are already utilized as the treatment against multiple sclerosis or inflammatory bowel diseases [There are currently no therapeutic strategies, such as the elimination of HTLV-1-infected CD4diseases , might hdiseases , might b


Glaucoma, the leading cause of irreversible blindness, is a common disorder that contributes to gradual optic nerve degeneration. The beneficial impacts of uric acid (UA) have been reported in some neurodegenerative conditions such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis. But the results of current studies about the association between serum UA level and glaucoma are conflicting. The present meta-analysis was conducted to provide a better understanding of the association between serum UA level and glaucoma.We searched the databases of PubMed, Scopus, Web of Science, and Google Scholar systematically until November 20, 2022 to identify case-control studies, comparing the serum UA concentrations of the patients with glaucoma and controls. The mean ± standard division difference was used to assess the difference in serum UA concentrations between the glaucoma patients and controls.I2 = 91.92%, 95% CI = −0.42 to 0.68) higher than the controls; however, it was not statistically significant.Six studies involving 1,221 glaucoma patients and 1,342 control group were included in the present meta-analysis. This meta-analysis using a random effect model indicated that the mean UA level in glaucoma patients was 0.13 (Our findings provide evidence that glaucoma patients have a higher serum UA level compared to the controls, but this difference is not statistically significant. Prospective studies are needed to determine the possible association between increased UA and glaucoma pathogenesis.https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022364055, identifier: CRD42022364055. Glaucoma is the leading cause of irreversible blindness in the world . The preIn the early stages, glaucoma might be asymptomatic, or patients may experience blurred or missing areas in their vision field . HoweverAlthough the harmful effects of glaucoma on vision are irreversible, early diagnosis and treatment of this condition can decrease the risk of permanent blindness .Due to the asymptomatic nature of glaucoma, early detection of the disease is challenging, and the number of diagnosed patients with glaucoma is lower than undiagnosed patients , 9.Intraocular pressure (IOP) measurement is one of the main diagnostic tests for the diagnosis and progress monitoring of glaucoma . EvaluatGlaucoma has traditionally been considered an eye disease, but recent studies have linked it to central nervous system degeneration –16. The The underlying pathogenesis of glaucomatous optic neuropathy is still unknown. It has been suggested that glaucoma destroys neurons through neuroinflammation and oxidative stress . Antioxiin-vitro by production and scavenging of reactive oxygen species (Uric acid (UA) is a purine metabolite that detects intracellularly and in all body fluids  and that species , 22. The species , Hunting species , Alzheim species , and amy species . HoweverBy exploring the association between uric acid and glaucoma, we can identify potential abnormal metabolic processes in glaucoma patients, thereby considering UA as a biomarker. Data from several case-control studies suggest a significant inverse association between serum concentrations of UA and glaucoma risk –29. HoweThe present study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) . The proin vivo in humans, and the subjects could be controls or glaucoma patients.The present systematic review focused on case-control studies that reported the serum UA concentrations in patients with glaucoma and compared them to controls. The investigations should be conducted We included only studies in the English language. We excluded conference meetings and abstracts that were not published in peer-reviewed journals. If original data or exact numbers were unavailable in both groups of patients with glaucoma and controls, they were not included in our quantitative analysis.To identify studies to be included in this review, a systematic search was performed via PubMed, Scopus, Google Scholar, and Web Of Science databases from inception through November 20, 2022. We used the following search strategy: (“uric acid”[Mesh]) AND (“glaucoma”[Mesh] OR “Intraocular Pressure”[Mesh] OR “Ocular Hypertension” [Mesh]). Moreover, the reference lists of studies obtained in the initial search were manually searched for more relevant articles.After removing duplicate records, two reviewers (MM and HRG) independently analyzed all titles and abstracts obtained from the searches to identify relevant papers.The full text of studies that appeared to meet the inclusion criteria were obtained and independently analyzed by two reviewers (MM and HG). The authors resolved the disagreement through a discussion with a third author (AS). Eventually, studies that did not meet the inclusion criteria were discarded.We applied the Newcastle-Ottawa Quality Assessment Scale (NOS) for case-control studies to evaluate the methodological quality of the studies . The NOSUsing standardized data extraction forms, two reviewers (MM and AS) extracted data independently. In cases of disagreement between the reviewers, a third reviewer (HG) was consulted. The following data were extracted from selected studies: authors' name, publication year, country of study, glaucoma type, number of subjects, age range of subjects, definition, and the mean and standard deviation of serum UA levels. Data were extracted separately for each entity groups (glaucoma patients or controls).I2 statistic measures were used for the evaluation of heterogeneity between studies. P-values < 0.05 for Cochran's Q test and an I2 higher than 25% will be considered as significant heterogeneity (The mean difference (MD) and its corresponding standard error (SE) were calculated by using the mean values and their standard deviations reported/calculated for case and control groups. Then MDs extracted from each study were used as effect size for meta-analysis. The meta-analyses were performed using DerSimonian-Laird random-effects model, which takes the between-study heterogeneity into account. Stata software, version 17.0 , was used to analyze the data. Both the Q statistic and ogeneity .P-values < 0.05 were considered statistically significant. To conduct a sensitivity analysis, each article was removed from the final analysis. Begg's funnel plots and Egger's and Begg's asymmetry tests were used to assess the presence of publication bias , Tunis (n = 1), Greece (n = 1), Italy (n = 1), and Japan (n = 1).Among six studies evaluating the level of UA in serum, 1,221 glaucoma patients were compared to the 1,342 control group. One study recruited patients with normal-tension glaucoma (NTG), another study with primary angle closure glaucoma (PACG), while the patients in the other four studies all were primary open-angle glaucoma (POAG). The largest sample size between these studies included 886 primary angle closure glaucoma patients, with 994 participants as a control group. In comparison, the smallest contained 23 primary open-angle glaucoma patients with 15 participants as a control group. These studies were performed in China  higher than the controls; however, it was not statistically significant   .So far, the association between serum UA concentrations and glaucoma is under debate. To the best of our knowledge, this is the first meta-analysis to examine the relationship between serum UA level and glaucoma.In the present meta-analysis of 1,221 glaucoma patients compared to 1,342 controls included in 6 case-control studies, serum UA concentration in patients with glaucoma was higher than in the controls, but this association was not statistically significant.Three out of six case-control studies –29 withiSome authors have recently found decreased total antioxidant capacity levels in the blood and aqueous humor samples of glaucoma patients , 38. OxiUA is one of the main antioxidants of plasma , 41. WayLi et al. investigated the association between the progression of recently diagnosed PACG and pretreatment UA levels of serum. In this prospective observational study, there was a correlation between a lower baseline serum UA concentration and a higher risk of PACG progression. These findings suggested that higher serum UA values may protect against PACG and suppress the disease progression .Heliobacter pylori infection and glaucoma  and controls and reported that serum UA levels of subjects with and without pseudoexfoliation were similar .The other three studies included in our meta-analysis –32 suggeRegarding this subject interestingly, elevated levels of UA have been reported in the aqueous humor of some patients with glaucoma . AdditioNevertheless, IOP elevation is insufficient to explain the underlying pathophysiology of glaucoma . Therefoin vitro and in vivo findings suggested that UA may contribute to endothelial dysfunction by causing antiproliferative impacts on the endothelium (According to the growing body of clinical and experimental research, UA-induced inflammatory response and oxidative stress contribute to microvascular impairments , 55. Somothelium , 57, whiothelium .Moreover, it has been reported that an elevated serum UA and its fluctuations were independently related to impaired choroidal and retinal microcirculation .In a recent study, Yang et al. reported that higher serum UA concentrations were noticeably associated with decreased retinal capillary plexus vessel density. These results may support the damaging impact of high serum UA concentrations on the retinal microvasculature and suggest the necessity of regulating serum UA to prevent microvascular alteration . In addiSerum UA is known as a potential risk factor for the development and progression of chronic renal disease. It has been reported that elevated serum UA levels can cause an increase in glomerular blood pressure leading to renal diseases. Additionally, pilot studies have suggested that lowering serum UA therapies may slow the progression of chronic renal disease . In thisWith all these interpretations, this study was a meta-analysis of the case-control studies, and we cannot consider a precise causal role for UA in the pathogenesis of glaucoma.Due to the limited number of primary studies available, we were unable to perform a separate analysis for UA levels in each glaucoma subtype. Therefore, it is important to interpret the results cautiously, considering the potential variations in UA levels among different glaucoma types.In addition, systemic diseases and some medications administration may affect the serum UA level –66. ExceThe observational nature of the included studies does not allow us to determine whether UA-lowering interventions can influence the development of glaucoma. Further randomized clinical trials are required to assess whether the UA-lowering medications may be beneficial in managing glaucoma.The primary objective of our study was to compare serum UA levels between patients with glaucoma and the control group. We did not analyze and compare the concentration of UA levels in the vitreous and/or aqueous humor. Prior studies have shown that UA levels in aqueous humor of patients with glaucoma were higher than controls , 50. TheFurthermore, the study population of included studies in our meta-analysis was limited, and it is necessary to conduct more extensive prospective cohort studies to determine the potential link between serum UA levels and glaucoma.This meta-analysis summarized a large body of evidence from case-control studies on the association between serum UA level and glaucoma. These findings provided evidence that serum UA concentrations are higher in glaucoma patients in comparison with controls, but this association is not statistically significant. However, prospective studies are needed to confirm the exact effect of serum UA concentrations on the risk of glaucoma.The original contributions presented in the study are included in the article/MM and HGho designed the study. HGha, MM, and AY performed a systematic search and extracted the data. AS-A and HGho conducted statistical analysis. MM, HGho, and MS drafted the paper. All authors read, revised the manuscript, contributed to the article, and approved the submitted version.


This study assessed fertility knowledge in adults with sickle cell disease using the Cardiff Fertility Knowledge Scale and Fertility Treatment Perception Survey and compared knowledge scores in respondents with sickle cell disease to previously reported unaffected cohorts.p < 0.05 for all analyses.This cross-sectional study surveyed adults over age 18 with sickle cell disease at an adult sickle cell disease center using a 35-question survey addressing infertility risk factor knowledge and perceptions of fertility treatment. Analyses included summary statistics for continuous and categorical variables, univariate linear regression, and Mann-Whitney U tests for group comparisons of Fertility Knowledge Scale scores. Fertility Treatment Perception Survey scores were measured by medians of the two positive statements and four negative statements to generate separate positive and negative treatment belief scores. Statistical significance was set at p = 0.001), and higher than in a cohort of reproductive-aged Black women in the USA . Less than 50% of respondents correctly identified common infertility risk factors including sexually transmitted infections, advanced age, and obesity. Mean positive fertility perception score was 3 , and negative fertility perception score was 3.5 . Factors associated with agreement with negative fertility perception statements included: trying to conceive, refusing sickle cell disease treatment, and undergoing fertility treatment.Ninety-two respondents  with median age of 32 years  completed the survey between October 2020-May 2021. Sixty-five percent of respondents reported taking sickle cell disease treatment and 18% reported refusing at least one sickle cell disease treatment due to fertility concerns. The mean Fertility Knowledge Score was 49% (SD: 5.2), lower than reported in an international cohort (57% vs. 49%, Opportunities exist to improve knowledge of infertility risk factors among adults with sickle cell disease. This study raises the possibility that nearly one in five adults with sickle cell disease refuse SCD treatment or cure due to infertility concerns. Education about common infertility risks factors needs to be addressed alongside disease- and treatment- associated fertility risks. Sickle cell disease (SCD) is a common, inherited autosomal recessive hematologic disorder with myriad life limiting complications . ImproveSCD treatments and cures are transformative and life-sustaining, and some jeopardize future fertility , 6, 7. HInfertility risks are a patient-centered SCD concern that impact use of transformative SCD treatments and cures –21. A stThe aim of this study was to assess fertility knowledge in adults with SCD using the Cardiff Fertility Knowledge Scale (CFKS) and Fertility Treatment Perception Survey , 25. A sThe Johns Hopkins Institutional Review Board approved this cross-sectional survey. We included adults with SCD aged 18 years or older and cared for at the Sickle Cell Center for Adults between October 10, 2020, and May 26, 2021. Initially we obtained oral consent during clinic visits. However, the COVID−19 pandemic impeded in-person recruitment and we subsequently recruited participants during telemedicine visits and after January 21, 2021, consented respondents received a survey link sent through the electronic medical record.The survey consisted of 35 questions including the CFKS and Fertility Treatment Perception Survey, questions assessing demographics, SCD treatment use, and reproductive outcomes . The FleThe CFKS is a 13-question survey that assesses knowledge of (1) causes for reduced fertility, (2) common misconceptions about fertility, and (3) basic facts about infertility. Answer choices are true, false, or do not know. True responses are considered correct, and false or do not know answers are considered incorrect. The total survey score is reported as a percentage of correct responses.The Fertility Perception Treatment survey is co-administered with the CFKS , 26 and U test with a Z-continuity correction of <0.05 was conducted to evaluate if the CFKS scores varied by demographic or reproductive characteristics and SCD treatment use. We compared CFKS scores to scores reported separately in international reproductive-aged populations  for continuous variables and frequencies for categorical variables are reported. Mann-Whitney ulations  and in rulations . We perfsion 9.4 .Over seven months, we contacted 435 eligible patients and 92 completed surveys, among them 71 self-identified female and 21 self-identified male (21% survey response rate).n = 38) and chronic red blood cell transfusion (n = 17), and recently approved drugs, crizanlizumab and voxelotor (n = 5). Three respondents, all women, had a history of unsuccessful HSCT. Although most respondents (82%) did not refuse SCD treatment or cure due to infertility concerns, 18% reported refusing one or more SCD treatment due to fertility concerns  endorsed using medical assistance to conceive, and among them, one person reported a successful conception.p = 0.001), and higher than a cohort of reproductive aged, unaffected Black women in Atlanta, Georgia in the U.S. . CFKS score among respondents trying to conceive (n = 6) was not different than in the international cohort of people trying to conceive (62% versus 57%).The average CFKS score was 49% , lower than an international cohort of men and women currently trying to conceive , those referred for fertility tests compared to those not referred (69% vs 46% p = 0.001), among fertility treatment recipients versus non-recipients , and among respondents who knew someone that used a fertility treatment compared to those who did not .Mean CFKS score was higher among respondents with secondary versus primary education . Mean CFKS score did not differ by sex (49% men vs. 44% women), age greater or less than 35 years (51% vs. 48%), status of trying to conceive versus not trying to conceive (58% vs. 49%), or by treatment choice .Correct responses to individual questions varied from 32% to 79% . Over 65The Fertility Treatment Perception survey assesses positive perceptions of fertility treatment (FT) using two items and negative perceptions of FT using four items. Higher summed scores indicate greater agreement with positive or negative statements. The median average positive fertility perception score was 3  and negative fertility perception score was 3.5 .p = .02).The median positive FT perception score was the same among men and women: 3.5. The median negative FT perception score was 3 for men and 4 for women. Responses to each question by all respondents and stratified by sex are shown in n = 32) compared to those taking hydroxyurea (n = 38) , or to those receiving chronic transfusions (n = 17) . Respondents taking hydroxyurea (n = 38) had higher median negative FT perception scores than those taking voxelotor, crizanlizumab, or chronic transfusions (n = 54) . Also, there were higher negative FT perception scores among respondents who refused SCD treatment due to fertility concerns (n = 17) compared to those who did not (n = 75) , respondents who were trying to conceive (n = 6) than those not trying to conceive (n = 86) , and among respondents with a history of fertility treatment (n = 6) compared to those who did not undergo fertility treatment (n = 86) .There were several other significant differences. There were higher positive FT perception scores among respondents not taking SCD treatment , 50% had been trying to conceive for over one year. Among them, only one respondent was referred for fertility testing, and had not conceived. Also, 17 respondents reported refusing at least one of the three most clearly transformational SCD interventions available, hydroxyurea, curative therapy, or transfusions, due to fertility concerns. As disease-specific fertility counseling and care interventions evolve, addressing infertility risks that affect the general population and SCD-specific risks is necessary . Additionally, selection bias is possible: this study may have attracted participation of people with fertility concerns. Those referred for fertility care, refusing treatment due to infertility concerns, and with failed HSCT may be overrepresented in this sample. The average educational attainment in this sample was high. For these reasons, possibly the CFKS scores reported in our sample are higher than the general SCD population. In addition, a small number of respondents were trying to conceive at the time of study. Fertility treatment outcomes were not obtained. In addition, both sample size and survey response rate was low, perhaps because we were forced to enroll subjects remotely due to the COVID−19 pandemic. This may reduce the generalizability to other adults with SCD, however the direction of those differences is unclear as there is limited research on this topic. The small number of participants also precluded meaningful multivariable regression analysis adjusting for sociodemographic characteristics. Further research with larger sample sizes investigating fertility knowledge, perceptions, and care is necessary. Study is also needed to compare the characteristics of people with SCD who do or do not pursue fertility care.A strength of this study includes the use of a validated survey tool with the opportunity for comparison to other groups. In addition, this is an understudied topic: very few studies have investigated fertility knowledge, perception, or fertility care among adults with SCD , 18, 24.As people with SCD may have both disease-specific and general infertility risks , counsel


Human T-lymphotropic virus 2 (HTLV-2) has been described for more than 30 years as an endemic infection in Brazilian indigenous populations, with its occurrence varying by age and sex, maintained mainly by sexual intercourse and mother-to-child transmission, favoring intrafamilial aggregation.The epidemiological scenario of HTLV-2 infection has been described among communities of the Amazon region of Brazil (ARB), with the number of retrospective positive blood samples increasing for more than 50 years.Five publications were selected that showed the presence of HTLV-2 in 24 of 41 communities; the prevalence of infection was described among 5,429 individuals at five points in time. Among the Kayapó villages, the prevalence rates were described according to age and sex and reached up to 41.2%. Three communities  were kept virus free for 27 to 38 years of surveillance. Low, medium and high prevalence levels of infection were defined, and two pockets of high endemicity were shown in the state of Pará, pointing to the Kikretum and Kubenkokrê Kayapó villages as the epicenter of HTLV-2 in the ARB.The prevalence rates over the years have shown a decline among the Kayapó (from 37.8 to 18.4%) and an apparent change to a higher prevalence among females, but not during the first decade of life, usually associated with transmission from mother to child. Sociocultural and behavioral aspects, as well as public health policies directed toward sexually transmitted infections, might have positively influenced the decline in HTLV-2 infections. High prMost reports have shown heterogeneous HTLV-2 infection among the distinct indigenous groups in the ARB, with seroprevalence rates ranging from 0 to 40% . In the 2.2.1.The present study is a descriptive epidemiological approach aiming to evaluate the prevalence rate of HTLV-2 infection along the period ranging from 1967 to 2022. There are few studies regarding the presence of HTLV-2 among indigenous peoples from the Amazon region of Brazil and some of them used samples that were previously collected and stored for other purposes. In the absence of available database, there was a selection of five major criteria that would represent the best approaches for transversal studies to define prevalence rates, as listed below.The prevalence level of infection in each community was rated as absent, low , medium (5.1 to 10%) or high (greater than 10.1%). The studies included in the present evaluation were those that (i) were clearly designed to provide global prevalence information on HTLV-2 in the ARB among indigenous communities ; (ii) included revisits to previously evaluated indigenous villages to provide two/three-point prevalence information; (iii) allowed the comparison of prevalence rates according to age and sex in a two-point prevalence investigation; (iv) used well defined antibody detection methods , with confirmation of the responses , for the purpose of presenting a strong seroepidemiological study; and (v) presented a reasonable sample in the original article.2.2.p value <0.05).Prevalence rates were defined by the number of individuals with the specified characteristics at a given point in time over the total number of individuals examined. Demographic information was collected from the articles included in this study for descriptive statistical analyses. Chi-square tests and Fisher’s exact tests were used to compare the general prevalence rates and the prevalence rates according to age and sex. BioEstat 5.3  was used3.Among the published manuscripts that dealt with the prevalence of HTLV-2 among indigenous peoples from the ARB, five studies were selected on the basis of the defined criteria, particularly the consistency in the sampling and in the use of laboratory methods that were capable of distinguishing between seroreactivity to HTLV-1 and HTLV-2.As listed in The general prevalence rates of HTLV-2 infection ranged from 5.7%  to 8.1% p < 0.0001). The highest rates were found among the Kikretum (41.2%) and Kubenkokrê (37.4%) in the 1990s and the Kubenkokrê (23.1%) in 2021.The prevalence rates among the Kayapó villages ranged from 11.0%  to 37.8%Seroreactivity to HTLV-1 was sporadically reported  and presp = 0.0009), females  and their sum in both studies  was statistically significant.The distribution of HTLV-2 according to age and sex among the Kayapó villages is shown in in utero or breastfeeding transmission. Significant differences were found when comparing males  between both studies but not females . The third comparison adding males and females from the two studies (21.6% vs. 7.6%) was also significantly different (p = 0.0137) from the comparison in the initial study published.The same approach was used to compare the prevalence rates during the first 9 years of life to have an approximate figure to indicate 4.The origin of HTLV-2 infection in the ARB, was previously proposed to be in close association with the intense migration of humans who crossed the Behring Strait and arrived in South America . The seaHTLV-2 is widely distributed in the ARB, but upon closer inspection, it is geographically distributed mainly within two pockets in the state of Para . The perUpon revisiting the Parakanã village, the virus was not present. It is possible that the sole person who was found to be positive in 1995 was not successful in further transmitting the virus. Although the Asurini, Araweté and Parakanã are geographically linked to one of these two major pockets of high endemicity of HTLV-2, it seems that the absence of contact among them, as a consequence of disputes for different reasons, was a sufficient containment measure that prevented dissemination of the virus .Whatever reasons that maintain the absence of HTLV-2 among the Kaapor, Palikur, Tembé, Asurini, Arara, Araweté, Parakanã, Juruna, Amanayé, Macushi, Surui, Baniwa, Ticuna, Kanamari and Pano should be investigated, and public health policies should be strongly recommended to maintain indigenous communities free from HTLV-1/2 infection.In contrast, low, middle, and high prevalence rates of HTLV-2 were observed among the Kayapó villages. Although HTLV-2 has been detected in eight states of the ARB, the vast majority of infected communities were located in the state of Pará, and the epicenter of the virus seemed to be within the Kayapó villages Kubenkokrê and Kokraimoro, which had the highest numbers of infections during two sequential visits. However, in the last visit , GorotirContinuous visits to the indigenous villages of the ARB starting in the 1980s, with a major and main objective of providing access to medical personnel, health aid and treatment coupled with surveillance of infectious diseases and vaccination coverage, showed us that a clearer clinical epidemiological picture is being depicted. Although the prevalence rates are still high in the two major pockets of hyperendemicity of HTLV-2, it seems that the prevalence of HTLV-2 has clearly declined from when the first samples were collected in 1966  to 2022 in utero or by breastfeeding. It is important to emphasize that in some cultures, cross-breastfeeding is a common cultural practice that positively impacts the spread of the virus among the individuals of the community, as an HTLV-infected mother is able to infect other children apart from their own. Family aggregation is a common event  to provide medical assistance in regard to genetic and chronic diseases, as well as bacterial and virus infections. Short visits (10–15 days) were arranged with a medical and research team to investigate the presence of maladies and to provide further assistance in the prevention and control of diseases, whenever possible. Prevention of infectious agents is a difficult task to achieve when it comes to sexual and breastfeeding transmission. According to their needs, several villages of indigenous groups were usually revisited to evaluate the clinical and epidemiological needs.The search for information regarding HTLV among indigenous populations was sometimes frustrating because of the small number of publications available. This limitation is a possible consequence of the authorities’ restrictions imposed to access the communities, the difficulties to reach most villages that are in geographical isolated areas and make it even more difficult to prepare prospective studies. Considering all these adverse conditions, the choice to prepare prevalence studies with multiple points of observation in time is the best option to evaluate the actual changes in the frequency of HTLV and other viral and bacterial infections.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico, CNPq .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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