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Shunji Tomatsu,1,2 Kazuki Sawamoto,1 Carlos J Alméciga-Díaz,3 Tsutomu Shimada,1 Michael B Bober,1 Yasutsugu Chinen,4 Hiromasa Yabe,5 Adriana M Montaño,6 Roberto Giugliani,7 Francyne Kubaski,1,8 Eriko Yasuda,1 Alexander Rodríguez-López,3 Angela J Espejo-Mojica,3 Oscar F Sánchez,9 Robert W Mason,1 Luis A Barrera,3 William G Mackenzie,1 Tadao Orii2 1Nemours/Alfred I duPont Hospital for Children, Wilmington, DE, USA; 2Department of Pediatrics, Gifu University, Gifu, Japan; 3Institute for the Study of Inborn Errors of Metabolism, School of Sciences, Pontificia Universidad Javeriana, Bogotá, Colombia; 4Department of Pediatrics, Faculty of Medicine, University of the Ryukyus, Okinawa, 5Department of Cell Transplantation and Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan; 6Department of Pediatrics, Saint Louis University, St Louis, MO, USA; 7Medical Genetics Service/HCPA and Department of Genetics/UFRGS, Porto Alegre, Brazil; 8Department of Biological Sciences, University of Delaware, Newark, DE, 9School of Chemical Engineering, Purdue University, West Lafayette, IN, USA Abstract: Patients with mucopolysaccharidosis IVA (MPS IVA) can present with systemic skeletal dysplasia, leading to a need for multiple orthopedic surgical procedures, and often become wheelchair bound in their teenage years. Studies on patients with MPS IVA treated by enzyme replacement therapy (ERT) showed a sharp reduction on urinary keratan sulfate, but only modest improvement based on a 6-minute walk test and no significant improvement on a 3-minute climb-up test and lung function test compared with the placebo group, at least in the short-term. Surgical remnants from ERT-treated patients did not show reduction of storage materials in chondrocytes. The impact of ERT on bone lesions in patients with MPS IVA remains limited. ERT seems to be enhanced in a mouse model of MPS IVA by a novel form of the enzyme tagged with a bone-targeting moiety. The tagged enzyme remained in the circulation much longer than untagged native enzyme and was delivered to and retained in bone. Three-month-old MPS IVA mice treated with 23 weekly infusions of tagged enzyme showed marked clearance of the storage materials in bone, bone marrow, and heart valves. When treatment was initiated at birth, reduction of storage materials in tissues was even greater. These findings indicate that specific targeting of the enzyme to bone at an early stage may improve efficacy of ERT for MPS IVA. Recombinant N-acetylgalactosamine-6-sulfate sulfatase (GALNS) in Escherichia coli BL21 (DE3) (erGALNS) and in the methylotrophic yeast Pichia pastoris (prGALNS) has been produced as an alternative to the conventional production in Chinese hamster ovary cells. Recombinant GALNS produced in microorganisms may help to reduce the high cost of ERT and the introduction of modifications to enhance targeting. Although only a limited number of patients with MPS IVA have been treated with hematopoietic stem cell transplantation (HSCT), beneficial effects have been reported. A wheelchair-bound patient with a severe form of MPS IVA was treated with HSCT at 15 years of age and followed up for 10 years. Radiographs showed that the figures of major and minor trochanter appeared. Loud snoring and apnea disappeared. In all, 1 year after bone marrow transplantation, bone mineral density at L2–L4 was increased from 0.372 g/cm2 to 0.548 g/cm2 and was maintained at a level of 0.48±0.054 for the following 9 years. Pulmonary vital capacity increased approximately 20% from a baseline of 1.08 L to around 1.31 L over the first 2 years and was maintained thereafter. Activity of daily living was improved similar to the normal control group. After bilateral osteotomies, a patient can walk over 400 m using hip–knee–ankle–foot orthoses. This long-term observation of a patient shows that this treatment can produce clinical improvements although bone deformity remained unchanged. In conclusion, ERT is a therapeutic option for MPS IVA patients, and there are some indications that HSCT may be an alternative to treat this disease. However, as neither seems to be a curative therapy, at least for the skeletal dysplasia in MPS IVA patients, new approaches are investigated to enhance efficacy and reduce costs to benefit MPS IVA patients. Keywords: mucopolysaccharidosis IVA, ERT, HSCT, skeletal dysplasia, keratan sulfate

This contribution highlights the emergence of a newly endemic region for scorpion envenoming in South America, covering eastern Bolivia, Paraguay, and the midwestern Brazilian states of Mato Grosso and Mato Grosso do Sul. These areas have not historically been known to harbor life-threatening scorpion species. Tityus confluens, a parthenogenetic species of medical significance in Argentina, has been identified in severe and lethal human cases in Bolivia and Paraguay. Given that the clinical use of scorpion antivenom preparations in the region has often lacked preclinical data and considering the significant burden of scorpion envenoming, we propose a panregional evaluation of available anti-Tityus antivenoms. This evaluation, along with interdisciplinary efforts at a multinational scale to control scorpionism, aims to determine their true neutralization capacity and potential clinical efficacy against known culprits in the Southern Cone of South America and other regions endemic for scorpion envenoming on the continent.

Background: Mexico is among the countries with the highest mortality rates by firearms worldwide. We aimed to analyse the trend in the burden of firearm violence (FV) by age and sex in Mexico at a national and subnational level, and the association between this burden and the Sociodemographic Index., Methods: We used estimates from the Global Burden of Disease (GBD)-2019 study for the analysis of FV mortality, premature mortality and disability for all available age-groups and by sex. The GBD data separates FV into three categories-interpersonal violence from firearms, unintentional injuries from firearms and self-harm from firearms. We used a joinpoint regression analysis to analyse the temporal trends of the FV burden., Results: FV exhibited a non-significant increase. By cause, there was a significant increase in the burden of interpersonal violence from firearms, a non-significant decrease in the burden of self-harm from firearms and a significant decrease in the burden of unintentional injuries from firearms. Most of the FV burden is attributed to interpersonal violence from firearms. Almost the entirety of the burden of FV results from premature mortality. The incidence of FV disability adjusted life years (DALYs) was significantly higher among males than females, and was most concentrated in males aged 20-44 and females aged 15-49. Significant heterogeneity in FV DALY trends was observed at the subnational level., Conclusion: These results may help to better understand the burden of FV and help the design and implementation of national and local preventive policies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: We aimed to analyse the trends of interpersonal violence (IV) in Latin America (LA) between 1990 and 2019 for females and males at a national level., Study Design: Cross-sectional descriptive study., Methods: Following the 2019 Global Burden of Disease study we report IV mortality, premature mortality, years lived with disability and disability-adjusted life-years (DALYs) in LA by sex. To estimate the DALYs trends, we conducted a Joinpoint regression analysis., Results: Across all LA countries, IV burden was higher among males. Most of the IV burden was attributable to premature death, with a higher percentage in men than women. The burden of IV was most pronounced within the 15 to 39 age-groups in the majority of countries. Physical violence (PV) by firearm was the main cause of IV in LA, followed by PV by other means. Women in LA experienced at least twice as many sexual violence DALYs as men. IV in LA exhibited heterogeneous trends, with certain countries witnessing a significant decline in the IV DALYs rate, while others displayed a significant increase., Conclusions: Our results show the great heterogeneity of IV burden present in the region as the trends varied from one country to another. Policing and criminal justice institutions in LA have failed to reduce crime and violence. Thus, tailored preventive measures and public policies that account for the specific context and geographical areas where this phenomenon is prevalent are urgently needed., (Copyright © 2024 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Morquio A disease is a genetic disorder resulting in N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, and patients are currently treated with enzyme replacement therapy via weekly intravenous enzyme infusions. A means of sustained enzyme delivery could improve patient quality of life by reducing the administration time, frequency of hospital visits, and treatment cost. In this study, we investigated poly(ethylene-glycol) (PEG) hydrogels as a tunable, hydrolytically degradable drug delivery system for the encapsulation and sustained release of recombinant human GALNS (rhGALNS). We evaluated hydrogel formulations that optimized hydrogel gelation and degradation time while retaining rhGALNS activity and sustaining rhGALNS release. We observed the release of active rhGALNS for up to 28 days in vitro from the optimized formulation. rhGALNS activity was preserved in the hydrogel relative to buffer over the release window, and encapsulation was found to have no impact on the rhGALNS structure when measured by intrinsic fluorescence, circular dichroism, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). In vivo, we monitored the retention of fluorescently labeled rhGALNS in C57BL/6 albino mice when administered via subcutaneous injection and observed rhGALNS present for up to 20 days when delivered in a hydrogel versus 7 days in the buffer control. These results indicate that PEG hydrogels are suitable for the encapsulation, preservation, and sustained release of recombinant enzymes and may present an alternative method of delivering enzyme replacement therapies that improve patient quality of life.

Objective: This study assessed growth patterns in patients with mucopolysaccharidosis (MPS) VII before enzyme replacement therapy., Methods: Height, weight, and body mass index (BMI) measurements and Z -scores from patients from three clinical studies were compared with those from CDC healthy population growth charts. Relationships with age/sex and history of non-immune hydrops fetalis (NIHF) were assessed by linear regression and ANOVA, respectively., Results: Among 20 enrolled patients with MPS VII, height Z -scores were near normal until 1 year of age but declined thereafter, particularly among males. There was no consistent pattern in weight Z -score. BMI Z -scores were above normal and increased slightly with age among males and were slightly below normal among females. Male patients with a history of NIHF had greater declines in height and weight Z -scores over time versus males without history of NIHF. There was no clear effect of NIHF history on height and weight Z -scores in female patients., Conclusions: In patients with MPS VII, declines in height Z -score began early in life, particularly among males, while changes in BMI varied by sex. Patients with MPS VII and a history of NIHF had greater declines in height Z -score with age than did patients without a history of NIHF. Clinical trial registration: This retrospective analysis included patients enrolled in an open-label phase 2 study (UX003-CL203; ClinicalTrials.gov, NCT02418455), a randomized, placebo-controlled, blind-start phase 3 study (UX003-CL301; ClinicalTrials.gov, NCT02230566), or its open-label, long-term extension (UX003-CL202; ClinicalTrials.gov, NCT02432144). Requests for individual de-identified participant data and the clinical study report from this study are available to researchers providing a methodologically sound proposal that is in accordance with the Ultragenyx data sharing commitment. To gain access, data requestors will need to sign a data access and use agreement. Data will be shared via secured portal. The study protocol and statistical analysis plan for this study are available on the relevant clinical trial registry websites with the tabulated results., Competing Interests: Adriana M. Montaño has received research support from 10.13039/100013220Ultragenyx Pharmaceutical Inc. Agnieszka Różdżyńska-Świątkowska declares no conflicts of interest. Agnieszka Jurecka, Antonio Nino Ramirez, Lin Zhang, and Deborah Marsden are employees of and own stock in Ultragenyx Pharmaceutical Inc. Raymond Y. Wang has received research support from Ultragenyx Pharmaceutical Inc. Paul Harmatz has received research and consulting support from Ultragenyx Pharmaceutical Inc., (© 2023 The Authors. Published by Elsevier Inc.)

Introduction: Morphologic features of the mandible are influenced by the genes of each individual. Mandible size is important to orthodontists because the mandible is the mechanism by which the lower face influences facial esthetics and dental function. To date, no biological marker has been identified that indicates eventual mandible size. This study aimed to correlate the expression of DLX5, DLX6, EDN1, HAND2, PRRX1, and MSX1 to mandible size., Methods: Fifty-nine orthodontic patients aged >6 years who had available cephalometric radiographs were studied. Patients were classified on the basis of condylion-to-gnathion measurements. Messenger RNA was isolated from saliva and subjected to real-time quantitative polymerase chain reaction., Results: Threshold cycle values for subjects with small mandibles (>1 standard deviation [SD] from the mean) had the least expression of DLX6 and MSX1. Threshold cycle values for subjects with large mandibles (>1 SD) had less expression of DLX6 and MSX1 than subjects within 1 SD but more than those with small mandibles., Conclusions: DLX6 and MSX1 are related to mandible development and size. This finding could be used to improve treatment planning for medical and dental professionals seeking to understand the impact of genetics on bone growth., (Copyright © 2022 American Association of Orthodontists. Published by Elsevier Inc. All rights reserved.)

Background: In June 2019, the Bolivian Ministry of Health reported a cluster of cases of hemorrhagic fever that started in the municipality of Caranavi and expanded to La Paz. The cause of these cases was unknown., Methods: We obtained samples for next-generation sequencing and virus isolation. Human and rodent specimens were tested by means of virus-specific real-time quantitative reverse-transcriptase-polymerase-chain-reaction assays, next-generation sequencing, and virus isolation., Results: Nine cases of hemorrhagic fever were identified; four of the patients with this illness died. The etiologic agent was identified as Mammarenavirus Chapare mammarenavirus , or Chapare virus (CHAPV), which causes Chapare hemorrhagic fever (CHHF). Probable nosocomial transmission among health care workers was identified. Some patients with CHHF had neurologic manifestations, and those who survived had a prolonged recovery period. CHAPV RNA was detected in a variety of human body fluids (including blood; urine; nasopharyngeal, oropharyngeal, and bronchoalveolar-lavage fluid; conjunctiva; and semen) and in specimens obtained from captured small-eared pygmy rice rats ( Oligoryzomys microtis ). In survivors of CHHF, viral RNA was detected up to 170 days after symptom onset; CHAPV was isolated from a semen sample obtained 86 days after symptom onset., Conclusions: M. Chapare mammarenavirus was identified as the etiologic agent of CHHF. Both spillover from a zoonotic reservoir and possible person-to-person transmission were identified. This virus was detected in a rodent species, O. microtis . (Funded by the Bolivian Ministry of Health and others.)., (Copyright © 2022 Massachusetts Medical Society.)

Cardiovascular disease (CVD) in Mucopolysaccharidosis Type IVA (Morquio A), signified by valvular disease and cardiac hypertrophy, is the second leading cause of death and remains untouched by current therapies. Enzyme replacement therapy (ERT) is the gold-standard treatment for MPS disorders including Morquio A. Early administration of ERT improves outcomes of patients from childhood to adulthood while posing new challenges including prognosis of CVD and ERT's negligible effect on cardiovascular health. Thus, having accurate biomarkers for CVD could be critical. Here we show that cathepsin S (CTSS) and elastin (ELN) can be used as biomarkers of extracellular matrix remodeling in Morquio A disease. We found in a cohort of 54 treatment naïve Morquio A patients and 74 normal controls that CTSS shows promising attributes as a biomarker in young Morquio A children. On the other hand, ELN shows promising attributes as a biomarker in adolescent and adult Morquio A. Plasma/urine keratan sulfate (KS), and urinary glycosaminoglycan (GAG) levels were significantly higher in Morquio A patients ( p < 0.001) which decreased with age of patients. CTSS levels did not correlate with patients' phenotypic severity but differed significantly between patients (median range 5.45-8.52 ng/mL) and normal controls (median range 9.61-15.9 ng/mL; p < 0.001). We also studied α -2-macroglobulin (A2M), C-reactive protein (CRP), and circulating vascular cell adhesion molecule-1 (sVCAM-1) in a subset of samples to understand the relation between ECM biomarkers and the severity of CVD in Morquio A patients. Our experiments revealed that CRP and sVCAM-1 levels were lower in Morquio A patients compared to normal controls. We also observed a strong inverse correlation between urine/plasma KS and CRP ( p = 0.013 and p = 0.022, respectively) in Morquio A patients as well as a moderate correlation between sVCAM-1 and CTSS in Morquio A patients at all ages ( p = 0.03). As the first study to date investigating CTSS and ELN levels in Morquio A patients and in the normal population, our results establish a starting point for more elaborate studies in larger populations to understand how CTSS and ELN levels correlate with Morquio A severity., Competing Interests: 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., (Copyright © 2022 Montavon, Winter, Gan, Arasteh and Montaño.)

Objective: To report four cases of hydrops fetalis secondary to congenital syphilis and carry out a review of the literature to answer the question, What is the antibiotic regimen used in cases of gestational syphilis with hydrops fetalis as a complication?, Materials and Methods: Four cases of congenital syphilis with hydrops fetalis are presented. Maternal age ranged between 17 and 28 years, gestational age at the time of diagnosis varied between 25 and 30 weeks, and two of the mothers had not initiated prenatal care at that time. Treatment with crystalline penicillin for gestational syphilis was given immediately 6 to 12 weeks before delivery in three cases and partners were prescribed treatment with benzathine penicillin. As for the neonates, two had no active infection or sequelae and one of them was considered to have congenital syphilis based on non-treponemal test titers. In one case, the patient was unable to receive syphilis treatment before delivery and her newborn had signs of active infection. A review of the literature was conducted in the Medline, LILACS and Google Scholar databases using the search terms “hydrops fetalis,” “Lues”, “syphilis – prenatal diagnosis - ultrasound - penicillin – treatment”. The search included case reports and case series or cohorts of newborns with gestational syphilis and hydrops fetalis. Information regarding treatment in the mothers and in the newborns was extracted., Results: Overall, 119 articles were identified. Of these, 13 met the inclusion criteria, three were discarded because the full text could not be accessed. Ten studies with a total of 16 reported cases of hydrops fetalis secondary to congenital infection were reported. Of these, three presented with severe fetal anemia and required intrauterine transfusion; 5 cases received intrauterine penicillin treatment. In four cases the mother received weekly intramuscular injections of benzathine penicillin for 3 weeks, one received additional intravenous crystalline penicillin for 13 days, while another one received intravenous crystalline penicillin for 14 days. Treatment during gestation was not given in a total of 11 cases; and 6 of the 16 cases (37.5%) resulted in perinatal death., Conclusion: Delays in prenatal care and late diagnosis and treatment of gestational syphilis are important causes of persistent congenital syphilis. Randomized studies are required to identify the best treatment in fetuses with congenital syphilis 30 days before delivery and in fetuses with systemic compromise during the second half of gestation.

Background: Mucopolysaccharidoses (MPS) are rare, inherited lysosomal storage disorders characterized by progressive multiorgan involvement. Previous studies on incidence and prevalence of MPS mainly focused on countries other than the United States (US), showing considerable variation by country. This study aimed to identify MPS incidence and prevalence in the US at a national and state level to guide clinicians and policy makers., Methods: This retrospective study examined all diagnosed cases of MPS from 1995 to 2015 in the US using the National MPS Society database records. Data included year of birth, patient geographic location, and MPS variant type. US population information was obtained from the National Center for Health Statistics. The incidence and prevalence rates were calculated for each disease. Incidence rates were calculated for each state., Results: We obtained information from 789 MPS patients during a 20-year period. Incidence of MPS in the US was found to be 0.98 per 100,000 live births. Prevalence was found to be 2.67 per 1 million. MPS I, II, and III had the highest incidence rate at birth (0.26/100,000) and prevalence rates of 0.70-0.71 per million. Birth incidences of MPS IV, VI, and VII were 0.14, 0.04 and 0.027 per 100,000 live births., Conclusions: This is the most comprehensive review of MPS incidence and prevalence rates in the US. Due to the large US population and state fragmentation, US incidence and prevalence were found to be lower than other countries. Nonetheless, state-level studies in the US supported these figures. Efforts should be focused in the establishment of a national rare disease registry with mandated reporting from every state as well as newborn screening of MPS.

Background: Mucopolysaccharidosis IVA (Morquio A syndrome) is a lysosomal storage disease caused by the deficiency of enzyme N-acetylgalactosamine-6-sulfate sulfatase (GALNS), which results in the accumulation of the glycosaminoglycans (GAGs), keratan sulfate, and chondroitin-6-sulfate in the lysosomes of all tissues causing systemic dysfunction. Current treatments include enzyme replacement therapy (ERT) which can treat only certain aspects of the disease such as endurance-related biological endpoints. A key challenge in ERT is ineffective enzyme uptake in avascular tissues, which makes the treatment of the corneal, cartilage, and heart valvular tissue difficult. The aim of this study was to culture human umbilical mesenchymal stem cells (UMSC), demonstrate presence of GALNS enzyme activity within the extracellular vesicles (EVs) derived from these UMSC, and study how these secreted EVs are taken up by GALNS-deficient cells and used by the deficient cell's lysosomes., Methods: We obtained and cultured UMSC from the umbilical cord tissue from anonymous donors from the Saint Louis Cord Blood Bank. We characterized UMSC cell surface markers to confirm phenotype by cell sorting analyses. In addition, we confirmed that UMSC secrete GALNS enzyme creating conditioned media for co-culture experiments with GALNS deficient cells. Lastly, we isolated EVs derived from UMSC by ultracentrifugation to confirm source of GALNS enzyme., Results: Co-culture and confocal microscopy experiments indicated that the lysosomal content from UMSC migrated to deficient cells as evidenced by the peak signal intensity occurring at 15 min. EVs released by UMSC were characterized indicating that the EVs contained the active GALNS enzyme. Uptake of GALNS within EVs by deficient fibroblasts was not affected by mannose-6-phosphate (M6P) inhibition, suggesting that EV uptake by these fibroblasts is gradual and might be mediated by a different means than the M6P receptor., Conclusions: UMSC can deliver EVs containing functional GALNS enzyme to deficient cells. This enzyme delivery method, which was unaffected by M6P inhibition, can function as a novel technique for reducing GAG accumulation in cells in avascular tissues, thereby providing a potential treatment option for Morquio A syndrome.

Importance: Injuries have been a major cause of premature mortality and short-term and long-term disability in Mexico., Objective: To report the findings from the Global Burden of Disease 2019 study on injuries in Mexico at a national and subnational scale from 1990 to 2019., Methods: Following the 2019 Global Burden of Disease study we examined injury mortality, premature mortality, years lived with disability and disability-adjusted life-years according to 14 subcategories. We calculated the Pearson correlation coefficient between the injury burden and the socio-demographic index., Results: While the number of deaths from injuries increased significantly, the changes in the age-standardized mortality rates trended towards declines. Interpersonal violence, road injuries, falls and self-harm accounted for 8 of every 10 deaths from injury in 2019. Injury mortality and the disability-adjusted life-years rates decreased nationally and in most states in the period as a whole, but have increased since 2007. The injury burden was higher for men in all age groups. Interpersonal violence caused the highest disability-adjusted life-years rate in males and road injuries in females. The socio-demographic index increased in all states, while the injury age-standardized disability-adjusted life-years rates between 1990 and 2019 decreased, but there was no statistical association between both indicators., Discussion and Conclusions: This study represents a comprehensive review of injury burden of disease in Mexico. The injury burden decreased, but improved heterogeneously among states. To further reduce the injury burden of disease, it's necessary for federal, state and local governments to prioritize safety promotion and injury prevention programs, infrastructure improvements, legislation, and enforcement at a national and subnational level. Mexico's injury prevention efforts should also be tailored for specific age groups, such as males aged 20-49 years or females in the younger and older age groups, and high-burden areas., Competing Interests: Declarations of Competing Interest None declared by the authors., (Copyright © 2021. Published by Elsevier Ltd.)

Mucopolysaccharidosis IVA (Morquio A disease) is a genetic disorder caused by deficiency of N-acetylgalactosamine-6-sulfate-sulfatase (GALNS), leading to accumulation of keratan sulfate and chondroitin-6-sulfate in lysosomes. Many patients become wheelchair-dependent as teens, and their life span is 20-30 years. Currently, enzyme replacement therapy (ERT) is the treatment of choice. Although it alleviates some symptoms, replacing GALNS enzyme poses several challenges including very fast clearance from circulation and instability at 37 °C. These constraints affect frequency and cost of enzyme infusion and ability to reach all tissues. In this study, we developed injectable and biodegradable polyethylene glycol (PEG) hydrogels, loaded with recombinant human GALNS (rhGALNS) to improve enzyme stability and bioavailability, and to sustain release. We established the enzyme's release profile via bulk release experiments and determined diffusivity using fluorescence correlation spectroscopy. We observed that PEG hydrogels preserved enzyme activity during sustained release for 7 days. In the hydrogel, rhGALNS diffused almost four times slower than in buffer. We further confirmed that the enzyme was active when released from the hydrogels, by measuring its uptake in patient fibroblasts. The developed hydrogel delivery device could overcome current limits of rhGALNS replacement and improve quality of life for Morquio A patients. Encapsulated GALNS enzyme in a polyethylene glycol hydrogel improves GALNS stability by preserving its activity, and provides sustained release for a period of at least 7 days.

Objective: To report the case of a partial molar pregnancy with live fetus and conduct a review of the literature regarding maternal and fetal complications associated to this condition., Methods: Case report of a partial mole with a 33 weeks live fetus complicated by intrauterine growth restriction, oligohydramnios and severe preeclampsia. We report satisfactory maternal and neonatal outcomes and 1-year follow-up. A search was conducted in the Medline via Pubmed, Lilacs, Ovid, Uptodate and Google Scholar databases using the following MESH terms: hiditadiform mole, partial mole, live fetus, coexisting live fetus. Case series and case reports of pregnant women with coexisting partial mole and live fetus at the time of diagnosis were selected and information regarding maternal and fetal prognosis was extracted., Results: Initially, 129 related titles were identified. Of these, 29 met the inclusion criteria, and 4 articles were excluded due to failed access to the full text. Overall, 31 reported cases were included; 9 ended in miscarriage, 8 in fetal demise or perinatal death, and 14 (45 %) resulted in a live neonate. The most frequent maternal complication was preeclampsia in 6 (19.35 %) cases., Conclusions: The coexistence of a partial mole with a live fetus poses a high risk of adverse perinatal outcomes and preeclampsia. The volume of information regarding this rare condition must be increased in order to better determine potential interventions in cases of euploid fetuses and to provide adequate counseling in clinical practice. Therefore, reporting these cases is important to build sufficient evidence about the natural course of this condition., Competing Interests: None declared, (Copyright© 2020 This is an open-access article distributed under the terms of the Creative Commons Attribution License by-nc-nd/4.0.)

Background: Cardiovascular disease frequently causes morbidity and mortality in mucopolysaccharidoses (MPS); however, cardiovascular anatomy and dysfunction in MPS IVA (Morquio A disease) is not well described. Consequently, the study aimed to compare carotid artery structure and elasticity of MPS IVA patients with other MPS patients and healthy control subjects, and quantitate frequency of MPS IVA cardiac structural and functional abnormalities., Methods: Prospective, multi-center echocardiogram and carotid ultrasound evaluations of 12 Morquio A patients were compared with other MPS and healthy control subjects. Average differences between groups were adjusted for age, sex, and height with robust variance estimation for confidence intervals and P-values., Results: Morquio A patients demonstrated significantly higher (P < 0.001) adjusted carotid intima-media thickness (cIMT), mean (SD) of 0.56 mm (0.03) compared to control subjects, 0.44 mm (0.04). The Morquio A cohort had significantly greater adjusted carotid elasticity (carotid cross-sectional compliance + 43%, P < 0.001; carotid incremental elastic modulus - 33%, P = 0.003) than control subjects and other MPS patients. Aortic root dilatation was noted in 56% of the Morquio A cohort, which also had highly prevalent mitral (73%) and aortic (82%) valve thickening, though hemodynamically significant valve dysfunction was less frequent (9%)., Conclusions: Increased carotid elasticity in Morquio A patients is an unexpected contrast to the reduced elasticity observed in other MPS. These Morquio A cIMT findings corroborate MPS IVA arterial post-mortem reports and are consistent with cIMT of other MPS. Aortic root dilatation in Morquio A indicates arterial elastin dysfunction, but their carotid hyperelasticity indicates other vascular intima/media components, such as proteoglycans, may also influence artery function. Studying MPS I and IVA model systems may uniquely illuminate the function of glycosaminoglycan-bearing proteoglycans in arterial health.

Immune response to therapeutic enzymes poses a detriment to patient safety and treatment outcome. Enzyme replacement therapy (ERT) is a standard therapeutic option for some types of mucopolysaccharidoses, including Morquio A syndrome caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency. Current protocols tolerize patients using cytotoxic immunosuppressives, which can cause adverse effects. Here we show development of tolerance in Morquio A mice via oral delivery of peptide or GALNS for 10 days prior to ERT. Our results show that using an immunodominant peptide (I10) or the complete GALNS enzyme to orally induce tolerance to GALNS prior to ERT resulted in several improvements to ERT in mice: (a) decreased splenocyte proliferation after in vitro GALNS stimulation, (b) modulation of the cytokine secretion profile, (c) decrease in GALNS-specific IgG or IgE in plasma, (d) decreased GAG storage in liver, and (e) fewer circulating immune complexes in plasma. This model could be extrapolated to other lysosomal storage disorders in which immune response hinders ERT.

Background: Denosumab is a fully human monoclonal antibody that binds to, and inhibits, the receptor activator of RANKL (TNFSF11) and might affect breast cancer biology, as shown by preclinical evidence. We aimed to assess whether denosumab combined with standard-of-care adjuvant or neoadjuvant systemic therapy and locoregional treatments would increase bone metastasis-free survival in women with breast cancer., Method: In this international, double-blind, randomised, placebo-controlled, phase 3 study (D-CARE), patients were recruited from 389 centres in 39 countries. We enrolled women (aged ≥ 18 years) with histologically confirmed stage II or III breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. On eligibility confirmation, investigators at each site telephoned an interactive voice response system to centrally randomly assign patients (1:1) based on a fixed stratified permuted block randomisation list (block size 4) to receive either denosumab (120 mg) or matching placebo subcutaneously every 3-4 weeks, starting with neoadjuvant or adjuvant chemotherapy, for about 6 months and then every 12 weeks for a total duration of 5 years. Stratification factors were breast cancer therapy, lymph node status, hormone receptor and HER2 status, age, and geographical region. The primary endpoint was the composite endpoint of bone metastasis-free survival. This trial is registered with ClinicalTrials.gov, NCT01077154., Findings: Between June 2, 2010, and Aug 24, 2012, 4509 women were randomly assigned to receive denosumab (n=2256) or placebo (n=2253) and included in the intention-to-treat analysis. The primary analysis of the study was done when all patients had the opportunity to complete 5 years of follow-up with an analysis data cutoff date of Aug 31, 2017. The primary endpoint of bone metastasis-free survival was not significantly different between the groups (median not reached in either group; hazard ratio 0·97, 95% CI 0·82-1·14; p=0·70). The most common grade 3 or worse treatment-emergent adverse events, reported in patients who had at least one dose of the investigational product (2241 patients with denosumab vs 2218 patients with placebo), were neutropenia (340 [15%] vs 328 [15%]), febrile neutropenia (112 [5%] vs 142 [6%]), and leucopenia (62 [3%] vs 61 [3%]). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2241 patients treated with denosumab versus four (<1%) of 2218 patients treated with placebo; treatment-emergent hypocalcaemia occurred in 152 (7%) versus 82 (4%). Two treatment-related deaths occurred in the placebo group due to acute myeloid leukaemia and depressed level of consciousness., Interpretation: Despite preclinical evidence suggesting RANKL inhibition might delay bone metastasis or disease recurrence in patients with early-stage breast cancer, in this study, denosumab did not improve disease-related outcomes for women with high-risk early breast cancer., Funding: Amgen., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The scope of this paper was to analyze the trends, impact on life expectancy and effect of the main associated socioeconomic factors with the death rate by homicide in Colombia between 2000 and 2014 at the state level, by gender and age groups. Standardized mortality rates and years of life lost among those under 85 years of age were calculated and multivariate regression analysis was performed using negative binomial fixed effects regression models with panel data to analyze the associated socioeconomic factors with the incidence of homicide. The reduction of the death rate by homicide in Colombia was corroborated, which was generalized at state level, though it did not occur homogenously. A higher mortality risk was found among males, particularly between 15 and 49 years of age. Economic growth and inequality were negatively associated with death rates by homicide; unemployment was positively associated; and poverty had no effect on the mortality rate. Investigating the main associated factors with homicidal violence is complex, but is indispensable due to its impact on economic and social development, given that it mainly affects the population of productive age, with broad public health consequences and at a high cost to healthcare services.

Objectives: Colombia is considered one of the most violent countries in the world even though homicide mortality has decreased since 2002. Mexico's homicide rate has tripled since 2008, after a period of decreasing mortality; this fact has been compared with Colombia in the 1990s and defined as a 'Colombianization' of violence in Mexico. We analyzed and compared the trend and impact of homicide mortality in Colombia and Mexico between 1998 and 2015., Study Design: Cross-sectional descriptive study., Methods: We calculated the standardized mortality rates and the years of life lost using data from the National Institute of Statistics and Geography in Mexico and the National Management Department of Statistics in Colombia. We used the joinpoint regression analysis to identify significant changes in the mortality trend., Results: During the 1990s, Colombia reached the highest homicide mortality rates in the world, but these rates have since decreased significantly. In Mexico, homicide mortality had a decreasing trend from 1998 to 2007; however, since 2008, the rate grew significantly, and although mortality tended to decrease after reaching its peak in 2011, a slight upturn was observed in 2015., Conclusions: We found that the trend in mortality in both countries has had certain similarities, such as the increase in mortality after the implementation of antidrug policies and the subsequent decrease; however, the political processes, the level of mortality reached, its impact on life expectancy, and its distribution by gender are dissimilar. We consider speaking of a 'Colombianization' of violence in Mexico to be inaccurate., (Copyright © 2018 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.)

Background: Targeting specific tissues remains a major challenge to the promise of gene therapy. For example, several strategies have failed to target adeno-associated virus 2 (AAV2) vectors, to bone. We have evaluated in vitro and in vivo the affinity of an AAV2 vector to bone matrix, hydroxyapatite (HA) to treat Mucopolysacccharidosis IVA., Methods: To increase vector affinity to HA, an aspartic acid octapeptide (D8) was inserted immediately after the N-terminal region of the VP2 capsid protein. The modified vector had physical titers and transduction efficiencies comparable to the unmodified vector., Results: The bone-targeting vector had significantly higher HA affinity and vector genome copies in bone than the unmodified vector. The modified vector was also released from HA, and its enzyme activity in bone, 3 months post infusion, was 4.7-fold higher than the unmodified vector., Conclusion: Inserting a bone-targeting peptide into the vector capsid increases gene delivery and expression in the bone without decreasing enzyme expression. This approach could be a novel strategy to treat systemic bone diseases.

There is limited information regarding the long-term outcomes of hematopoietic stem cell transplantation (HSCT) for mucopolysaccharidosis II (MPS II). In this study, clinical, biochemical, and radiologic findings were assessed in patients who underwent HSCT and/or enzyme replacement therapy (ERT). Demographic data for 146 HSCT patients were collected from 27 new cases and 119 published cases and were compared with 51 ERT and 15 untreated cases. Glycosaminoglycan (GAG) levels were analyzed by liquid chromatography tandem mass spectrometry in blood samples from HSCT, ERT, and untreated patients as well as age-matched controls. Long-term magnetic resonance imaging (MRI) findings were investigated in 13 treated patients (6 ERT and 7 HSCT). Mean age at HSCT was 5.5 years (range, 2 to 21.4 years) in new patients and 5.5 years (range, 10 months to 19.8 years) in published cases. None of the 27 new patients died as a direct result of the HSCT procedure. Graft-versus-host disease occurred in 8 (9%) out of 85 published cases, and 9 (8%) patients died from transplantation-associated complications. Most HSCT patients showed greater improvement in somatic features, joint movements, and activity of daily living than the ERT patients. GAG levels in blood were significantly reduced by ERT and levels were even lower after HSCT. HSCT patients showed either improvement or no progression of abnormal findings in brain MRI while abnormal findings became more extensive after ERT. HSCT seems to be more effective than ERT for MPS II in a wide range of disease manifestations and could be considered as a treatment option for this condition., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Mucopolysaccharidoses (MPS) are a group of inborn errors of metabolism that are progressive and usually result in irreversible skeletal, visceral, and/or brain damage, highlighting a need for early diagnosis., Methods: This pilot study analyzed 2862 dried blood spots (DBS) from newborns and 14 DBS from newborn patients with MPS (MPS I, n = 7; MPS II, n = 2; MPS III, n = 5). Disaccharides were produced from polymer GAGs by digestion with chondroitinase B, heparitinase, and keratanase II. Heparan sulfate (0S, NS), dermatan sulfate (DS) and mono- and di-sulfated KS were measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). Median absolute deviation (MAD) was used to determine cutoffs to distinguish patients from controls. Cutoffs were defined as median + 7× MAD from general newborns., Results: The cutoffs were as follows: HS-0S > 90 ng/mL; HS-NS > 23 ng/mL, DS > 88 ng/mL; mono-sulfated KS > 445 ng/mL; di-sulfated KS > 89 ng/mL and ratio di-KS in total KS > 32 %. All MPS I and II samples were above the cutoffs for HS-0S, HS-NS, and DS, and all MPS III samples were above cutoffs for HS-0S and HS-NS. The rate of false positives for MPS I and II was 0.03 % based on a combination of HS-0S, HS-NS, and DS, and for MPS III was 0.9 % based upon a combination of HS-0S and HS-NS., Conclusions: Combination of levels of two or more different GAGs improves separation of MPS patients from unaffected controls, indicating that GAG measurements are potentially valuable biomarkers for newborn screening for MPS.

Background: Mucopolysaccharidosis VII (MPS VII) is an ultra-rare disease characterised by the deficiency of β-glucuronidase (GUS). Patients' phenotypes vary from severe forms with hydrops fetalis, skeletal dysplasia and mental retardation to milder forms with fewer manifestations and mild skeletal abnormalities. Accurate assessments on the frequency and clinical characteristics of the disease have been scarce. The aim of this study was to collect such data., Methods: We have conducted a survey of physicians to document the medical history of patients with MPS VII. The survey included anonymous information on patient demographics, family history, mode of diagnosis, age of onset, signs and symptoms, severity, management, clinical features and natural progression of the disease., Results: We collected information on 56 patients from 11 countries. Patients with MPS VII were classified based on their phenotype into three different groups: (1) neonatal non-immune hydrops fetalis (NIHF) (n=10), (2) Infantile or adolescent form with history of hydrops fetalis (n=13) and (3) Infantile or adolescent form without known hydrops fetalis (n=33). Thirteen patients with MPS VII who had the infantile form with history of hydrops fetalis and survived childhood, had a wide range of clinical manifestations from mild to severe. Five patients underwent bone marrow transplantation and one patient underwent enzyme replacement therapy with recombinant human GUS., Conclusions: MPS VII is a pan-ethnic inherited lysosomal storage disease with considerable phenotypical heterogeneity. Most patients have short stature, skeletal dysplasia, hepatosplenomegaly, hernias, cardiac involvement, pulmonary insufficiency and cognitive impairment. In these respects it resembles MPS I and MPS II. In MPS VII, however, one unique and distinguishing clinical feature is the unexpectedly high proportion of patients (41%) that had a history of NIHF. Presence of NIHF does not, by itself, predict the eventual severity of the clinical course, if the patient survives infancy., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The aim of this study was to evaluate the activity of daily living (ADL) and surgical interventions in patients with mucopolysaccharidosis IVA (MPS IVA). The factor(s) that affect ADL are age, clinical phenotypes, surgical interventions, therapeutic effect, and body mass index. The ADL questionnaire comprises three domains: "Movement," "Movement with cognition," and "Cognition." Each domain has four subcategories rated on a 5-point scale based on the level of assistance. The questionnaire was collected from 145 healthy controls and 82 patients with MPS IVA. The patient cohort consisted of 63 severe and 17 attenuated phenotypes (2 were undefined); 4 patients treated with hematopoietic stem cell transplantation (HSCT), 33 patients treated with enzyme replacement therapy (ERT) for more than a year, and 45 untreated patients. MPS IVA patients show a decline in ADL scores after 10years of age. Patients with a severe phenotype have a lower ADL score than healthy control subjects, and lower scores than patients with an attenuated phenotype in domains of "Movement" and "Movement with cognition." Patients, who underwent HSCT and were followed up for over 10years, had higher ADL scores and fewer surgical interventions than untreated patients. ADL scores for ERT patients (2.5years follow-up on average) were similar with the-age-matched controls below 10years of age, but declined in older patients. Surgical frequency was higher for severe phenotypic patients than attenuated ones. Surgical frequency for patients treated with ERT was not decreased compared to untreated patients. In conclusion, we have shown the utility of the proposed ADL questionnaire and frequency of surgical interventions in patients with MPS IVA to evaluate the clinical severity and therapeutic efficacy compared with age-matched controls., Competing Interests: Conflict of interestAll the authors contributed to the Original Article and had no conflict of interest with any other party. Eriko Yasuda, Suzuki Yasuyuki, Kazuki Sawamoto, Tsutomu Shimada, William G. Mackenzie, Mary Theroux, Christian Pizarro, Freeman Miller, Heidi H. Kecskemethy, Kyoko Nagao, Thierry Morlet, Tariq Rahman, Thomas Shaffer, Yasutsugu Chinen, Hiromasa Yabe, Akemi Tanaka, Kenji E. Orii, Koji O. Orii, Robert W. Mason, AdrianaM. Montaño, Tadao Orii, and Shunji Tomatsu declare that they have no conflict of interests., (Copyright © 2016. Published by Elsevier Inc.)

The objective of this study was to analyze mortality due to the main external causes of death (traffic accidents, other accidents, homicides and suicides) in Mexico, calculating the years of life lost between 0 and 100 years of age and their contribution to the change in life expectancy between 2000 and 2013, at the national level, by sex and age group. Data came from mortality vital statistics of the Instituto Nacional de Estadística y Geografía (INEGI) [National Institute of Statistics and Geography]. The biggest impact in mortality due to external causes occurred in adolescent and adult males 15-49 years of age; mortality due to these causes remained constant in males and slightly decreased in females. Mortality due to traffic accidents and other accidents decreased, with a positive contribution to life expectancy, but this effect was canceled out by the increase in mortality due to homicides and suicides. Mortality due to external causes can be avoided through interventions, programs and prevention strategies as well as timely treatment. It is necessary to develop multidisciplinary studies on the dynamics of the factors associated with mortality due to these causes.

The aim of this study was to assess the activities of daily living (ADL) in patients with Hunter syndrome (mucopolysaccharidosis II; MPS II) using a newly designed ADL questionnaire. We applied the questionnaire to evaluate clinical phenotypes and therapeutic efficacies of enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT). We also explored early signs and symptoms to make early diagnosis feasible. We devised a new ADL questionnaire with three domains: "movement," "movement with cognition," and "cognition." Each domain has four subcategories rated on a 5-point scale based on level of assistance. We also scored signs and symptoms unique to MPS by 12 subcategories (five points per category), providing 60 points in total. The questionnaire was first administered to 138 healthy Japanese controls (0.33-50 years), and successively, to 74 Japanese patients with Hunter syndrome (4-49 years). The patient cohort consisted of 51 severe and 23 attenuated phenotypes; 20 patients treated with HSCT, 23 patients treated early with ERT (≤8 years), 25 patients treated late with ERT (>8 years), and 4 untreated patients. Among 18 severe phenotypic patients treated by HSCT, 10 were designated as early HSCT (≤5years), while 8 were designated as late HSCT (>5years). Scores from patients with severe phenotypes were lower than controls and attenuated phenotypes in all categories. Among patients with severe phenotypes, there was a trend that HSCT provides a higher ADL score than early ERT, and there was a significant difference in ADL scores between late ERT and HSCT groups. Early ERT and early HSCT provided a higher score than late ERT and late HSCT, respectively. In conclusion, we have evaluated the feasibility of a new questionnaire in control population and patients with Hunter syndrome, leading to a novel evaluation method for clinical phenotypes and therapeutic efficacy. Early treatment with HSCT provides a better consequence in ADL of patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We treated mucopolysaccharidosis IVA (MPS IVA) mice to assess the effects of long-term enzyme replacement therapy (ERT) initiated at birth, since adult mice treated by ERT showed little improvement in bone pathology [1]. To conduct ERT in newborn mice, we used recombinant human N-acetylgalactosamine-6-sulfate sulfatase (GALNS) produced in a CHO cell line. First, to observe the tissue distribution pattern, a dose of 250units/g body weight was administered intravenously in MPS IVA mice at day 2 or 3. The infused enzyme was primarily recovered in the liver and spleen, with detectable activity in the bone and brain. Second, newborn ERT was conducted after a tissue distribution study. The first injection of newborn ERT was performed intravenously, the second to fourth weekly injections were intraperitoneal, and the remaining injections from 5th to 14th weeks were intravenous into the tail vein. MPS IVA mice treated with GALNS showed clearance of lysosomal storage in the liver and spleen, and sinus lining cells in bone marrow. The column structure of the growth plate was organized better than that in adult mice treated with ERT; however, hyaline and fibrous cartilage cells in the femur, spine, ligaments, discs, synovium, and periosteum still had storage materials to some extent. Heart valves were refractory to the treatment. Levels of serum keratan sulfate were kept normal in newborn ERT mice. In conclusion, the enzyme, which enters the cartilage before the cartilage cell layer becomes mature, prevents disorganization of column structure. Early treatment from birth leads to partial remission of bone pathology in MPS IVA mice., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Patients with mucopolysaccharidoses (MPS) have accumulation of glycosaminoglycans in multiple tissues which may cause coarse facial features, mental retardation, recurrent ear and nose infections, inguinal and umbilical hernias, hepatosplenomegaly, and skeletal deformities. Clinical features related to bone lesions may include marked short stature, cervical stenosis, pectus carinatum, small lungs, joint rigidity (but laxity for MPS IV), kyphoscoliosis, lumbar gibbus, and genu valgum. Patients with MPS are often wheelchair-bound and physical handicaps increase with age as a result of progressive skeletal dysplasia, abnormal joint mobility, and osteoarthritis, leading to 1) stenosis of the upper cervical region, 2) restrictive small lung, 3) hip dysplasia, 4) restriction of joint movement, and 5) surgical complications. Patients often need multiple orthopedic procedures including cervical decompression and fusion, carpal tunnel release, hip reconstruction and replacement, and femoral or tibial osteotomy through their lifetime. Current measures to intervene in bone disease progression are not perfect and palliative, and improved therapies are urgently required. Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy are available or in development for some types of MPS. Delivery of sufficient enzyme to bone, especially avascular cartilage, to prevent or ameliorate the devastating skeletal dysplasias remains an unmet challenge. The use of an anti-inflammatory drug is also under clinical study. Therapies should start at a very early stage prior to irreversible bone lesion, and damage since the severity of skeletal dysplasia is associated with level of activity during daily life. This review illustrates a current overview of therapies and their impact for bone lesions in MPS including ERT, HSCT, gene therapy, and anti-inflammatory drugs., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Keratan sulfate (KS) is a storage material in mucopolysaccharidosis IV (MPS IV). However, no detailed analysis has been reported on subclasses of KS: mono-sulfated KS and di-sulfated KS. We established a novel method to distinguish and quantify mono- and di-sulfated KS using liquid chromatography-tandem mass spectrometry and measured both KS levels in various specimens.Di-sulfated KS was dominant in shark cartilage and rat serum, while mono-sulfated KS was dominant in bovine cornea and human serum. Levels of both mono- and di-sulfated KS varied with age in the blood and urine from control subjects and patients with MPS II and IVA. The mean levels of both forms of KS in the plasma/serum from patients with MPS II, IVA, and IVB were elevated compared with that in age-matched controls. Di-sulfated KS provided more significant difference between MPS IVA and the age-matched controls than mono-sulfated KS. The ratio of di-sulfated KS to total KS in plasma/serum increased with age in control subjects and patients with MPS II but was age independent in MPS IVA patients. Consequently, this ratio can discriminate younger MPS IVA patients from controls. Levels of mono- and di-sulfated KS in urine of MPS IVA and IVB patients were all higher than age-matched controls for all ages studied.In conclusion, the level of di-sulfated KS and its ratio to total KS can distinguish control subjects from patients with MPS II, IVA, and IVB, indicating that di-sulfated KS may be a novel biomarker for these disorders.

Objective: To analyze the level and trend of diabetes mellitus (DM) in Mexico, and its contribution to the changes in temporary life expectancy between 20 and 100 years of age, in the period 1990-2010., Materials and Methods: Data comes from National Mortality Vital Statistics and from the Population Census from the Mexican National Institute of Geography and Statistics (INEGI). We calculated standardized mortality rates. To analyze the impact of DM on the temporary life expectancy (80e20) we used Pollard’s method., Results: Between 1990 and 2010, the standardized mortality rate for people 20 years and older increased by 224 %. The contribution of DM for men to the change in life expectancy during 1990-2000 was a reduction of 0.31 years; for women was a reduction of 0.32 years; in the period 2000-2010 the reduction continued for both men and women (0.34 and 0.12 years respectively)., Conclusions: Mortality from DM continues to increase, especially for men, but for women a modest reduction was observed. It is essential to apply health services and programs aimed at reducing mortality from this cause, focused on prevention, early detection and timely treatment, with concrete actions on vulnerable groups.