Erratum to "Overhydroxylation of Lysine of Collagen Increases Uterine Fibroids Proliferation: Roles of Lysyl Hydroxylases, Lysyl Oxidases, and Matrix Metalloproteinases".

[This corrects the article DOI: 10.1155/2017/5316845.].

The evaluation of operating Animal Bite Treatment Centers in the Philippines from a health provider perspective.

BACKGROUND: The Philippine government has an extensive network of 513 Animal Bite Treatment Centers (ABTCs) to supply rabies post exposure prophylaxis (PEP), reaching over 1 million bite victims in 2016. The network was evaluated using a review of existing national and provincial data, key informant interviews and surveys in sample ABTCs to determine the cost-effectiveness of this network in preventing human rabies deaths. METHODOLOGY AND PRINCIPAL FINDINGS: One urban and one rural ABTC in each of three selected provinces were studied in more detail. PEP delivery generally followed national guidance based on best practices, but there was evidence of operational challenges in supplying all ABTCs with adequate biologics and recently trained staff. Funding was contributed by different levels of government and in some clinics, patients paid for a significant fraction of the total cost. From a health provider perspective including both fixed and variable costs, the average PEP course delivered cost USD 32.91 /patient across urban ABTCs (with higher patient throughput) and USD 57.21 /patient across rural ABTCs. These costs suggests that PEP provision in the Philippines cost USD 37.6 million in 2016, with a cost per life saved of USD 8,290. An analysis of the 2,239 suspected rabies deaths from 2008 to 2016 showed no significant decline, and from 2014-16 an average of 8,534 years of life were lost annually. The incidence of rabies deaths from 2014-16 was not clearly related to the provision of ABTCs (per 100,000 population) or human population density, but deaths were more common in higher income provinces. CONCLUSIONS/SIGNIFICANCE: In the context of comprehensive rabies control (including dog vaccination and public awareness) ways to reduce this high expenditure on PEP should be explored, to most cost-effectively reach the elimination of human rabies deaths. This paper is accompanied by another containing data on the operation of ABTCs network from a patient perspective.

The evaluation of Animal Bite Treatment Centers in the Philippines from a patient perspective.

BACKGROUND: The Philippines has built an extensive decentralised network of Animal Bite Treatment Centers (ABTCs) to help bite victims receive timely rabies post-exposure prophylaxis (PEP) at little cost. This study surveyed patients in the community and at ABTCs of three provinces to assess animal bite/scratch incidence, health-seeking behaviour and PEP-related out-of pocket expenses (OOPE). METHODOLOGY AND PRINCIPAL FINDINGS: During community surveys in 90 barangays (neighbourhoods), 53% of households reported at least one animal bite /scratch injury over the past 3 years, similar across urban and rural barangays. Overall bite/scratch incidences in 2016-17 were 67.3, 41.9 and 48.8 per 1,000 population per year for Nueva Vizcaya, Palawan and Tarlac respectively. Incidences were around 50% higher amongst those under 15 years of age, compared to -those older than 15. Household awareness of the nearest ABTCs was generally over 80%, but only 44.9% sought proper medical treatment and traditional remedies were still frequently used. The proportion of patients seeking PEP was not related to the distance or travel time to the nearest ABTC. For those that did not seek medical treatment, most cited a lack of awareness or insufficient funds and almost a third visited a traditional healer. No deaths from bite/scratch injuries were reported. A cohort of 1,105 patients were interviewed at six ABTCs in early 2017. OOPE varied across the ABTCs, from 5.53 USD to 37.83 USD per patient, primarily dependent on the need to pay for immunization if government supplies had run out. Overall, 78% of patients completed the recommended course, and the main reason for non-completion was a lack of time, followed by insufficient funds. Dog observation data revealed that 85% of patients were not truly exposed to rabies, and education in bite prevention might reduce provoked bites and demand for PEP. An accompanying paper details the ABTC network from the health provider's perspective.

Overhydroxylation of Lysine of Collagen Increases Uterine Fibroids Proliferation: Roles of Lysyl Hydroxylases, Lysyl Oxidases, and Matrix Metalloproteinases.

The role of the extracellular matrix (ECM) in uterine fibroids (UF) has recently been appreciated. Overhydroxylation of lysine residues and the subsequent formation of hydroxylysylpyridinoline (HP) and lysylpyridinoline (LP) cross-links underlie the ECM stiffness and profoundly affect tumor progression. The aim of the current study was to investigate the relationship between ECM of UF, collagen and collagen cross-linking enzymes [lysyl hydroxylases (LH) and lysyl oxidases (LOX)], and the development and progression of UF. Our results indicated that hydroxyl lysine (Hyl) and HP cross-links are significantly higher in UF compared to the normal myometrial tissues accompanied by increased expression of LH (LH2b) and LOX. Also, increased resistance to matrix metalloproteinases (MMP) proteolytic degradation activity was observed. Furthermore, the extent of collagen cross-links was positively correlated with the expression of myofibroblast marker (α-SMA), growth-promoting markers (PCNA; pERK1/2; FAKpY397; Ki-67; and Cyclin D1), and the size of UF. In conclusion, our study defines the role of overhydroxylation of collagen and collagen cross-linking enzymes in modulating UF cell proliferation, differentiation, and resistance to MMP. These effects can establish microenvironment conducive for UF progression and thus represent potential target treatment options of UF.

Placenta Percreta and Incomplete Uterine Rupture after Endometrial Ablation and Tubal Occlusion.

Endometrial ablation offers symptomatic relief for menorrhagia. Pregnancy after ablation is rare but is often complicated due to pregnancy loss, growth restriction, preterm premature rupture of membranes, preterm delivery, and morbidly adherent placentation, a dangerous complication that can result in hemorrhage, intensive care unit admission, and cesarean hysterectomy. We report a case of pregnancy conceived contemporaneously with endometrial ablation and tubal occlusion. Diagnosis of pregnancy was delayed due to low suspicion. Complications included cervical implantation and placenta percreta, necessitating hysterectomy with the fetus in situ. Intraoperatively, incomplete uterine rupture was noted. Abnormal neovascularization, fibrous adhesions, and anatomical distortion necessitated a complex surgical approach. Women undergoing endometrial ablation must be thoroughly counseled about the serious risks of postablation pregnancy, the need for contraception, and the risk of sterilization failure. Pregnancy should remain in the differential diagnosis for women of reproductive age, regardless of tubal occlusion. Cases of placenta percreta should be referred early to centers of excellence with multidisciplinary teams.

Design and Measurement of Nonislet-Specific Autoantibodies for the Type 1 Diabetes Genetics Consortium Autoantibody Workshop.

The Type 1 Diabetes Genetics Consortium (T1DGC) comprised groups of investigators from many countries throughout the world, with a common goal of identifying genes predisposing to type 1 diabetes. The T1DGC ascertained and collected samples from families with two or more affected siblings with type 1 diabetes and generated a broad array of clinical, genetic, and immunologic data. The T1DGC Autoantibody Workshop was designed to distribute data for analyses to discover genes associated with autoantibodies in those with type 1 diabetes. In the T1DGC-affected sibling pair families, three T1DGC Network laboratories measured antibodies to the islet autoantigens GAD65 and the intracellular portion of protein tyrosine phosphatase (IA-2A). The availability of extensive genetic data provided an opportunity to investigate the associations between type 1 diabetes and other autoimmune diseases for which autoantibodies could be measured. Measurements of additional nonislet autoantibodies, including thyroid peroxidase, tissue transglutaminase, 21-hydroxylase, and the potassium/hydrogen ion transporter H+/K+-ATPase, were performed by the T1DGC laboratory at the Barbara Davis Center for Childhood Diabetes, Aurora, CO. Measurements of all autoantibodies were transmitted to the T1DGC Coordinating Center, and the data were made available to members of the T1DGC Autoantibody Working Groups for analysis in conjunction with existing T1DGC genetic data. This article describes the design of the T1DGC Autoantibody Workshop and the quality-control procedures to maintain and monitor the performance of each laboratory and provides the quality-control results for the nonislet autoantibody measurements.

Maternal morbidity in patients with morbidly adherent placenta treated with and without a standardized multidisciplinary approach.

OBJECTIVE: The purpose of this study was to test the hypothesis that a standardized multidisciplinary treatment approach in patients with morbidly adherent placenta, which includes accreta, increta, and percreta, is associated with less maternal morbidity than when such an approach is not used (nonmultidisciplinary approach). STUDY DESIGN: A retrospective cohort study was conducted with patients from 3 tertiary care hospitals from July 2000 to September 2013. Patients with histologically confirmed placenta accreta, increta, and percreta were included in this study. A formal program that used a standardized multidisciplinary management approach was introduced in 2011. Before 2011, patients were treated on a case-by-case basis by individual physicians without a specific protocol (nonmultidisciplinary group). Estimated blood loss, transfusion of packed red blood cells, intraoperative complications (eg, vascular, bladder, ureteral, and bowel injury), neonatal outcome, and maternal postoperative length of hospital stay were compared between the 2 groups. RESULTS: Of 90 patients with placenta accreta, 57 women (63%) were in the multidisciplinary group, and 33 women (37%) were in the nonmultidisciplinary group. The multidisciplinary group had more cases with percreta (P = .008) but experienced less estimated blood loss (P = .025), with a trend to fewer blood transfusions (P = .06), and were less likely to be delivered emergently (P = .001) compared with the nonmultidisciplinary group. Despite an approach of indicated preterm delivery at 34-35 weeks of gestation, neonatal outcomes were similar between the 2 groups. CONCLUSION: The institution of a standardized approach for patients with morbidly adherent placentation by a specific multidisciplinary team was associated with improved maternal outcomes, particularly in cases with more aggressive placental invasion (increta or percreta), compared with a historic nonmultidisciplinary approach. Our standardized approach was associated with fewer emergency deliveries.

The Philippines Field Management Training Program (FMTP): strengthening management capacity in a decentralized public health system.

OBJECTIVES: The decentralization of the Philippines' health sector in 1991 sought to improve the efficiency of local health resource allocation; however, local officials were unprepared for the increased responsibility. In 1999 the Philippines Department of Health, with assistance from the US Centers for Disease Control and Prevention (CDC), implemented the Philippines Field Management Training Program (FMTP) to provide local health officials with the managerial skills needed to perform their new, more responsible jobs. This paper addresses whether the FMTP has provided participants with useful managerial skills needed for their more responsible positions. METHODS: The method involved reviewing program outcomes, including results of applied management improvement projects the participants completed to solve managerial problems. RESULTS: Between 2000 and 2010, 294 participants completed the FMTP and many were later promoted to more responsible positions. The participants also completed 204 applied management improvement projects resulting in documented improvements in service delivery, information systems, logistics, health insurance, policy and laboratory outcomes. Examples of their successes are included in this paper. CONCLUSIONS: The results provide compelling evidence that managers are using the skills learned to solve significant managerial problems.

Estradiol-17ß upregulates pyruvate kinase M2 expression to coactivate estrogen receptor-α and to integrate metabolic reprogramming with the mitogenic response in endometrial cells.

CONTEXT: Proliferating cells reprogram their cellular glucose metabolism to meet the bioenergetic and biosynthetic demands and to maintain cellular redox homeostasis. Pyruvate kinase M (PKM) is a critical regulator of this metabolic reprogramming. However, whether estradiol-17ß (E2) reprograms cellular metabolism to support proliferation of human primary endometrial stromal cells (hESCs) and the molecular basis of this reprogramming are not well understood. OBJECTIVES: Our objectives were to study whether E2 induces reprogramming of glucose metabolism in hESCs and to investigate the potential roles of PKM2 in E2-induced metabolic reprogramming and proliferation of these cells. METHODS: The oxygen consumption rate and extracellular acidification rate were assessed by a Seahorse XF24 analyzer. PKM2 expression was assessed by real-time RT-PCR and immunoblotting. RESULTS: E2 induces a Warburg-like glucose metabolism in hESCs by inducing the expression of PKM. E2 also enhanced PKM splicing into the PKM2 isoform by upregulating the c-Myc-hnRNP axis. Furthermore, E2 induces PKM2 oxidation, phosphorylation, and nuclear translocation. In addition to its glycolytic function, PKM2 physically interacted with estrogen receptor-α (ERα) and functioned as an ERα coactivator. Small-molecule PKM2 activators ameliorated ERα transcriptional activity and abrogated the E2-induced hESC proliferation. CONCLUSIONS: We show for the first time that E2-induced hESC proliferation is associated with a shift in glucose metabolism toward aerobic glycolysis, and the molecular basis for this metabolic shift is linked to the effects of E2 on PKM2. In addition, PKM2 acts as a transcriptional coactivator for ERα and small-molecule PKM2 activators inhibit ERα transcriptional activity and reduce E2-induced cell proliferation.

2-Methoxyestradiol causes functional repression of transforming growth factor ß3 signaling by ameliorating Smad and non-Smad signaling pathways in immortalized uterine fibroid cells.

OBJECTIVE: To investigate the effects and the mechanism of action of 2-methoxyestradiol (2ME(2)) on transforming growth factor (TGF) ß3-induced profibrotic response in immortalized human uterine fibroid smooth muscle (huLM) cells. DESIGN: Laboratory study. SETTING: University research laboratory. PATIENTS(S): Not applicable. INTERVENTIONS(S): Not applicable. MAIN OUTCOME MEASURE(S): huLM cells were treated with TGF-ß3 (5 ηg/mL) in the presence or absence of specific Smad3 inhibitor SIS3 (1 µmol/L), inhibitor of the PI3K/Akt (LY294002, 10 µmol/L), or 2ME(2) (0.5 µmol/L), and the expression of collagen (Col) type I(αI), Col III(αI), plasminogen activator inhibitor (PAI) 1, connective tissue growth factor (CTGF), and α-smooth muscle actin (α-SMA) were determined by real-time reverse-transcription polymerase chain reaction and immunoblotting. The effect of 2ME(2) on Smad-microtubule binding was evaluated by coimmunoprecipitation. RESULT(S): Our data revealed that TGF-ß3-induced fibrogenic response in huLM is mediated by both Smad-dependent and Smad-independent PI3K/Akt/mTOR signaling pathways. 2ME(2) abrogates TGF-ß3-induced expression of Col I(αI), Col III(αI), PAI-1, CTGF, and α-SMA. Molecularly, 2ME(2) ameliorates TGF-ß3-induced Smad2/3 phosphorylation and nuclear translocation. In addition, 2ME(2) inhibits TGF-ß3-induced activation of the PI3K/Akt/mTOR pathway. CONCLUSION(S): TGF-ß3-induced profibrotic response in fibroid cells is mediated by Smad-dependent and Smad-independent PI3K/Akt/mTOR pathways. 2ME(2) inhibits TGF-ß3 profibrotic effects in huLM cells by ameliorating both Smad-dependent and Smad-independent signaling pathways.

[Teaching experience of the anesthesiology training unit at Hospital Universitario Nuestra Señora de Candelaria]. / Experiencia de la unidad docente de Anestesiología y Reanimación del Hospital Universitario Nuestra Señora de Candelaria.

BACKGROUND: Health care in Spain has improved progressively and professionals are now required to meet competency levels that safeguard the citizen's right to health protection. To achieve this, instructors in residency training programs and resident physicians themselves are calling for a common framework for training to ensure quality and consistency. Given the scarcity of articles related to training in our journal and following the First Meeting of Residency Program Instructors of the Sociedad Española de Anestesiologia y Reanimación (SEDAR), there has arisen a need to explain how SEDAR's training unit is organized. METHODS: In order to facilitate the sharing of experiences of those involved in training anesthesiology medical residents, we undertook a descriptive analysis of our hospital's curriculum. RESULTS: The structure and operation of the department are described in this report. The results of anonymous surveys completed annually show the satisfaction of residents (9.4 out of 10) and physicians (8.7 out of 10). An audit by the Ministry of Health showed that the curriculum met 100% of the required criteria.

The effect of tamoxifen and raloxifene on estrogen metabolism and endometrial cancer risk.

Selective estrogen receptor modulators (SERMs) demonstrate differential endometrial cancer (EC) risk. While tamoxifen (TAM) use increases the risk of endometrial hyperplasia and malignancy, raloxifene (RAL) has neutral effects on the uterus. How TAM increases the risk of EC and why TAM and RAL differentially modulate the risk for EC, however, remain elusive. Here, we tested the hypothesis that TAM increases the risk for EC, at least in part, by enhancing the local estrogen biosynthesis and directing estrogen metabolism towards the formation of genotoxic and hormonally active estrogen metabolites. In addition, the differential effects of TAM and RAL in EC risk are attributed to their differential effect on estrogen metabolism/metabolites. The endometrial cancer cell line (Ishikawa cells) and the nonmalignant immortalized human endometrial glandular cell line (EM1) were used for the study. The profile of estrogen/estrogen metabolites (EM), depurinating estrogen-DNA adducts, and the expression of estrogen-metabolizing enzymes in cells treated with 17ß-estradiol (E2) alone or in combination with TAM or RAL were investigated using high performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS(2)), ultraperformance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS), and Western blot analysis, respectively. TAM significantly increased the total EM and enhanced the formation of hormonally active and carcinogenic estrogen metabolites, 4-hydroxestrone (4-OHE1) and 16α-hydroxyestrone, with concomitant reduction in the formation of antiestrogenic and anticarcinogenic 2-hydroxyestradiol and 2-methoxyestradiol. Furthermore, TAM increased the formation of depurinating estrogen-DNA adducts 4-OHE1 [2]-1-N7Guanine and 4-OHE1 [2]-1-N3 Adenine. TAM-induced alteration in EM and depurinating DNA adduct formation is associated with altered expression of estrogen metabolizing enzymes CYP1A1, CYP1B1, COMT, NQO1, and SF-1 as revealed by Western blot analysis. In contrast to TAM, RAL has minimal effect on EM, estrogen-DNA adduct formation, or estrogen-metabolizing enzymes expression. These data show that TAM perturbs the balance of estrogen-metabolizing enzymes and alters the disposition of estrogen metabolites, which can explain, at least in part, the mechanism for TAM-induced EC. These results also implicate the differential effect of TAM and RAL on estrogen metabolism/metabolites as a potential mechanism for their disparate effects on the endometrium.

Experiencia de la unidad docente de Anestesiología y Reanimación del Hospital Universitario Nuestra Señora de Candelaria / Teaching experience of the anesthesiology training unit at Hospital

Objetivos: La sanidad en España ha evolucionado hacia una mejora de la calidad, exigiendo a los profesionales que cumplan los niveles de competencia necesarios para salvaguardar el derecho a la protección de la salud de los ciudadanos. Para alcanzarlos, las Unidades Docentes y los Médicos Residentes demandan un marco común de formación que garantice la calidad y la uniformidad de la docencia. Dado el escaso número de publicaciones en nuestra revista relacionadas con la docencia y tras la Primera Reunión de Tutores de Anestesiología y Reanimación de la SEDAR, surgió la inquietud por dar a conocer cómo tenemos organizada nuestra Unidad Docente. Métodos: Con el objetivo de facilitar el intercambio de experiencia de los implicados en la formación de los Médicos Internos Residentes de Anestesiología, Reanimación y Terapéutica del Dolor realizaremos un análisis descriptivo de la formación en nuestro hospital. Resultados: Se describe la estructura y funcionamiento. Las encuestas anónimas realizadas anualmente por los residentes (9,4 puntos sobre 10) y facultativos (8,7 sobre 10) muestran la aceptación del sistema. Además en una auditoría docente del Ministerio de Sanidad se ha cumplido el 100% de los criterios exigidos(AU)

Background: Health care in Spain has improved progressively and professionals are now required to meet competency levels that safeguard the citizen’s right to health protection. To achieve this, instructors in residency training programs and resident physicians themselves are calling for a common framework for training to ensure quality and consistency. Given the scarcity of articles related to training in our journal and following the First Meeting of Residency Program Instructors of the Sociedad Española de Anestesiología y Reanimación (SEDAR), there has arisen a need to explain how SEDAR’s training unit is organized. Methods: In order to facilitate the sharing of experiences of those involved in training anesthesiology medical residents, we undertook a descriptive analysis of our hospital’s curriculum. Results: The structure and operation of the department are described in this report. The results of anonymous surveys completed annually show the satisfaction of residents (9.4 out of 10) and physicians (8.7 out of 10). An audit by the Ministry of Health showed that the curriculum met 100% of the required criteria(AU)

Prognostic significance of peritumoral lymphatic vessel density and vascular endothelial growth factor receptor 3 in invasive squamous cell cervical cancer.

Cervical cancer is known to metastasize primarily by the lymphatic system. Dissemination through lymphatic vessels represents an early step in regional tumor progression, and the presence of lymphatic metastasis is associated with a poor prognosis. In patients who have undergone a radical hysterectomy, lymphovascular space invasion (LVSI), assessed on hematoxylin and eosin-stained slides, is a major factor for adjuvant therapy in patients with cervical cancer. With the advent of a lymphatic endothelial cell-specific marker, such as D2-40, it is now possible to distinguish between blood and lymphatic space invasion (LSI). In this study, the utility of D2-40 was assessed for the detection of lymphatic vessel density (LVD) and identification of LSI. The expressions of vascular endothelial growth factor receptor-3 (VEGFR-3), VEGF-C, tyrosine receptor kinase-2, and angiopoietin-1 were assessed by immunohistochemical methods on 50 patients with squamous cell carcinoma of the cervix. Clinicopathologic characteristics, including pelvic lymph node metastasis, were correlated with the above histochemical findings. We found that lymphangiogenesis, measured by an increase in peritumoral LVD, was significantly associated with positive lymph node status (P < .005). VEGFR-3 expression was significantly associated with LVD (P < .05). D2-40 staining verified LSI (P = .03) and surpassed that of hematoxylin and eosin-identified LVSI (P = .54). In conclusion, lymphangiogenic markers, specifically LVD quantified by D2-40 and VEGFR-3, are independently associated with LSI and lymph node metastasis in patients with early squamous cell carcinoma of the cervix treated with radical hysterectomy and pelvic lymphadenectomy.

Traqueotomía percutánea asistida con fibrobroncoscopio a través del dispositivo supraglótico I-gel / No disponible

No disponible

Catechol-o-methyltransferase expression and 2-methoxyestradiol affect microtubule dynamics and modify steroid receptor signaling in leiomyoma cells.

CONTEXT: Development of optimal medicinal treatments of uterine leiomyomas represents a significant challenge. 2-Methoxyestradiol (2ME) is an endogenous estrogen metabolite formed by sequential action of CYP450s and catechol-O-methyltransferase (COMT). Our previous study demonstrated that 2ME is a potent antiproliferative, proapoptotic, antiangiogenic, and collagen synthesis inhibitor in human leiomyomas cells (huLM). OBJECTIVES: Our objectives were to investigate whether COMT expression, by the virtue of 2ME formation, affects the growth of huLM, and to explore the cellular and molecular mechanisms whereby COMT expression or treatment with 2ME affect these cells. RESULTS: Our data demonstrated that E(2)-induced proliferation was less pronounced in cells over-expressing COMT or treated with 2ME (500 nM). This effect on cell proliferation was associated with microtubules stabilization and diminution of estrogen receptor alpha (ERalpha) and progesterone receptor (PR) transcriptional activities, due to shifts in their subcellular localization and sequestration in the cytoplasm. In addition, COMT over expression or treatment with 2ME reduced the expression of hypoxia-inducible factor -1alpha (HIF-1 alpha) and the basal level as well as TNF-alpha-induced aromatase (CYP19) expression. CONCLUSIONS: COMT over expression or treatment with 2ME stabilize microtubules, ameliorates E(2)-induced proliferation, inhibits ERalpha and PR signaling, and reduces HIF-1 alpha and CYP19 expression in human uterine leiomyoma cells. Thus, microtubules are a candidate target for treatment of uterine leiomyomas. In addition, the naturally occurring microtubule-targeting agent 2ME represents a potential new therapeutic for uterine leiomyomas.