Common Approaches of Cytochrome P450 (CYP) Induction Assays

The induction of enzymes is a defensive mechanism for some xenobiotics, but it may alter the drug's safety and efficacy by altering the activity of metabolic enzymes. One of the major families of enzymes involved in phase I metabolism is Cytochrome P450 (CYP) enzymes which may get induced by certain drugs. Concomitant administration of drugs due to chronic disease or polypharmacy, inducers among them may cause toxicity or reduce the plasma concentration at a sub-therapeutic level. This is one of the dangerous types of drug-drug interactions, but predictable & preventable. The CYPs get induced by three nuclear receptors, including the aryl hydrocarbon receptor (AhR); constitutive androstane receptor (CAR); the pregnane X receptor (PXR). Without identification during drug development, enzyme induction phenomenon of a new drug molecule may get noticed only during pharmacovigilance. Though, this CYP induction may not be a barrier for drug development, it may cause possible DDI and treatment failure. According to FDA guidelines, pharmaceutical industries adopted In-vitro, Ex-vivoand In-vivotechniques based on different developmental stages. The results are also interpreted based on regulatory bodies guidelines. For In-vitroassay best accepted method is using primary hepatocytes either fresh or cryopreserved, for Ex-vivoliver slices of different species and in-vivo, clinical investigations are the extreme option. This paper reviews current industry approaches of CYP induction assays to evaluate potentiality for a new drug molecule as an inducer

Third‑line chemotherapy after resistance to Etoposide, Cisplatin‑ Etoposide, Methotrexate, Actinomycin (EP‑EMA) in high risk gestational trophoblastic neoplasia: Experience at the Philippine General Hospital / Philippine Journal of Obstetrics and Gynecology

Objective@#To describe the experience of the Division of Trophoblastic Diseases of the Philippine General Hospital with the various third‑line chemotherapeutic regimens among high‑risk gestational trophoblastic neoplasia (GTN) patients who experienced resistance after receiving the etoposide, cisplatin–etoposide, methotrexate, actinomycin (EP‑EMA) regimen@*Materials and Methods@#This was a 17‑year descriptive study that included all patients who used various salvage chemotherapy after resistance to EP‑EMA as treatment for metastatic, high‑risk GTN at the Philippine General Hospital from January 2002 to December 2018. The medical records of eligible patients were retrieved and assessed. All abstracted data were analyzed retrospectively. Descriptive statistics were used to compute for percentages for the various demographic characteristics of the sample population@*Results@#From January 2002 to December 2018, a total of 291 patients with metastatic, high‑risk gestational GTN were treated at the Philippine General Hospital. Of these, only seven patients received various third‑line chemotherapy regimens after resistance to EP‑EMA. One patient was excluded due to incomplete data. Among the third‑line chemotherapeutic regimens used, 3 patients received paclitaxel/carboplatin, two of whom went into remission while one expired. One patient had vincristine, bleomycin, and cisplatin (VBP) with two adjunctive surgeries in the form of hysterectomy and thoracotomy. She also went into remission. Two patients received paclitaxel–cisplatin/paclitaxeletoposide (TP/TE) as third line of treatment. The first was shifted back to EP‑EMA and eventually developed chemoresistance to EP‑EMA and had multiple toxicities. After multidisciplinary conference with the patient and family, they decided to go home and refused further chemotherapy. The other patient had TP/TE followed by bleomycin–etoposide–cisplatin, with adjunctive hysterectomy. Despite multiple cycles of chemotherapy, the disease persisted. She was offered palliative care and the family decided to bring her home. Both patients eventually expired at home@*Conclusion@#No conclusion can be made about the most effective third line chemotherapy for resistant high‑risk GTN because of the limited cases included in this study. An individualized approach is still recommended. Physicians and centers for patients caring for such patients are encouraged to report their experience to improve the management of future patients

Uterine rescue in high-risk gestational trophoblastic neoplasia treated with ema-co by uterine arteries embolization due to arteriovenous malformations / Resgate uterino em neoplasia trofoblástica gestacional de alto risco tratada com EMA-CO por embolização de artérias uterinas devido a malformações arteriovenosas

Abstract Complete hydatidiform mole (CHM) is a rare type of pregnancy, in which 15 to 20% of the cases may develop into gestational trophoblastic neoplasia (GTN). The diagnostic of GTN must be done as early as possible through weekly surveillance of serum hCG after uterine evacuation.We report the case of 23-year-old primigravida, with CHM but without surveillance of hCG after uterine evacuation. Two months later, the patient presented to the emergency with vaginal bleeding and was referred to the Centro de Doenças Trofoblásticas do Hospital São Paulo. She was diagnosed with high risk GTN stage/score III:7 as per The International Federation of Gynecology and Obstetrics/World Health Organization (FIGO/WHO). The sonographic examination revealed enlarged uterus with a heterogeneous mass constituted of multiple large vessels invading and causing disarrangement of the myometrium. The patient evolved with progressive worsening of vaginal bleeding after chemotherapy with etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA-CO) regimen. She underwent blood transfusion and embolization of uterine arteries due to severe vaginal hemorrhage episodes, with complete control of bleeding. The hCG reached a negative value after the third cycle, and there was a complete regression of the anomalous vascularization of the uterus as well as full recovery of the uterine anatomy. The treatment in a reference center was essential for the appropriate management, especially regarding the uterine arteries embolization trough percutaneous femoral

Resumo Mola hidatiforme completa (MHC) é um tipo raro de gravidez, na qual 15 a 20% dos casos podem desenvolver neoplasia trofoblástica gestacional (NTG). O diagnóstico de NTG deve ser feito o mais cedo possível, pelo monitoramento semanal do hCG sérico após esvaziamento uterino. Relatamos o caso de uma paciente primigesta, de 23 anos de idade, com MHC, sem vigilância de hCG após esvaziamento uterino. Dois meses depois, a paciente compareceu na emergência com sangramento vaginal, sendo encaminhada ao Centro de Doenças Trofoblásticas do Hospital São Paulo, onde foi diagnosticada com NTG de alto risco, estádio e score de risco III:7 de acordo com a The International Federation of Gynecology and Obstetrics/Organização Mundial de Saúde (FIGO/OMS). O exame ultrassonográfico revelou útero aumentado com uma massa heterogênea constituída pormúltiplos vasos volumosos invadindo e desestruturando o miométrio. A paciente evoluiu com piora progressiva do sangramento vaginal após quimioterapia com o regime etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA-CO). Ela foi submetida a transfusão de sangue e embolização das artérias uterinas devido aos episódios graves de hemorragia vaginal, com completo controle do sangramento. O hCG atingiu valor negativo após o terceiro ciclo, havendo regressão completa da vascularização uterina anômala, assim como recuperação da anatomia uterina. O tratamento em um centro de referência permitiu o manejo adequado, principalmente no que se refere à embolização das artérias uterinas através da punção percutânea da artéria femoral, que foi crucial para evitar a histerectomia, permitindo a cura da NTG e a manutenção da vida reprodutiva.

Analysis of innovative drug category 1.2 in traditional Chinese medicine and considerations on quality control of extracts / 中国中药杂志

In this article, the essence of innovative drug category 1.2 extracts and preparations in the new version of the New Drug Registration Category of traditional Chinese medicines(TCM) was analyzed by combing through the history of provisions on drug registration and comparing with other categories of drugs. After analyzing the characteristics of this type of preparations, the author concluded that the quality control objectives of category 1.2 extract should focus on ensuring the quality consistency of the active ingredients/components in batches, so as to guarantee the consistency of drug quality and efficacy. With reference to the relevant technical requirements for herbal medicinal products in European Medicines Agency(EMA) and botanicals in Food and Drug Administration(FDA),the key points in quality control of the extract should include the content and composition of the therapeutic constituents, the type and content of the concomitants, and the influence of exogenous contaminants on drug safety.

Factors affecting remission to salvage chemotherapy with EtoposideCisplatin/Etoposide-MethotrexateActinomycin D (EP-EMA regimen) among chemoresistant high-risk Gestational Trophoblastic Neoplasia patients admitted in a tertiary institution: A 10-year retrospective descriptive study / Philippine Journal of Obstetrics and Gynecology

Background@#Approximately 20%–25% of high-risk gestational trophoblastic neoplasia (GTN) patients initially treated with first-line chemotherapy regimen develop resistance to the regimen. The EP-EMA (Etoposide-cisplatin and etoposide, methotrexate and actinomycin D) regimen is the most commonly utilized second-line agent. @*Objective@#This study aimed to identify factors leading to remission using etoposide and cisplatin-etoposide, methotrexate, and Actinomycin D (EP-EMA) as salvage chemotherapy among resistant high-risk GTN.@*Methods@#This is a retrospective descriptive study that reviewed the medical records of patients admitted in the section of trophoblastic diseases diagnosed with high-risk GTN from January 2006 to December 2015. @*Results@#The medical records of 20 patients were retrieved and reviewed. The complete remission rate with EP-EMA is 60% (12/20). The overall survival rate for 1 year is 70% (14/20). Only 20% of the patients went home against advice and did not complete treatment. This regimen reported toxicities ranging from Grade 2–4 myelosuppression and electrolyte imbalance. Forty-five percent had Grade 4 neutropenia and Grade 2 anemia and 20% had Grade 2 thrombocytopenia. Hypokalemia and hypomagnesemia were noted in 8 patients (40%). Although not statistically significant, a trend showed that those in the remission group mostly had Stage III diseases with metastasis only in the lungs, prognostic score of between 7 and 12, and with beta-human chorionic gonadotropin (β-hCG) levels <10,000 mIu/ml at the start of EP-EMA treatment.@*Conclusion@#There is an improved response with EP-EMA chemotherapy across the years in our institution. Factors such as stage of disease, pulmonary metastasis, and low β-hCG at the start EP-EMA chemotherapy denote a possible good response and may contribute to patients' complete remission with EP-EMA chemotherapy. However, further studies with larger patient sample size are recommended to support the latter.

Morphogenesis of the rhea (Rhea americana) respiratory system in different embryonic and foetal stages / Morfogênese do sistema respiratório da ema (Rhea americana) em diferentes estágios embrionários e fetais

The rhea (Rhea americana) is an important wild species that has been highlighted in national and international livestock. This research aims to analyse embryo-foetal development in different phases of the respiratory system of rheas. Twenty-three embryos and foetuses were euthanized, fixed and dissected. Fragments of the respiratory system, including the nasal cavity, larynx, trachea, syrinx, bronchi and lungs, were collected and processed for studies using light and scanning electron microscopy. The nasal cavity presented cubic epithelium in the early stages of development. The larynx exhibited typical respiratory epithelium between 27 and 31 days. The trachea showed early formation of hyaline cartilage after 15 days. Syrinx in the mucous membrane of 18-day foetuses consisted of ciliated epithelium in the bronchial region. The main bronchi had ciliated epithelium with goblet cells in the syringeal region. In the lung, the parabronchial stage presented numerous parabronchi between 15 and 21 days. This study allowed the identification of normal events that occur during the development of the rhea respiratory system, an important model that has not previously been described. The information generated here will be useful for the diagnosis of pathologies that affect this organic system, aimed at improving captive production systems.(AU)

A ema (Rhea americana) representa importante espécie silvestre que vem se destacando na pecuaria nacional e internacional. Esta pesquisa objetiva analisar o desenvolvimento embrionário-fetal, em diferentes fases, do sistema respiratório de emas. Vinte e três embriões e fetos foram eutanasiados, fixados e dissecados. Fragmentos do sistema respiratório: cavidade nasal, laringe, traqueia, siringe, brônquios e pulmões, foram coletados e processados para estudos por meio de microscopia de luz e microscopia eletrônica de varredura. A cavidade nasal apresentou, nas primeiras fases de desenvolvimento, epitélio estratificado cúbico. A laringe exibiu epitélio respiratório típico entre 27 e 31 dias. A traqueia aos 15 dias apresentou início de formação da cartilagem hialina. Na siringe a túnica mucosa de fetos de 18 dias e formada por epitélio estratificado ciliado na região bronquial. Os brônquios principais apresentavam epitélio estratificado ciliado com células caliciformes na região siringeal. No pulmão, o estágio parabronquial apresentou numerosos parabrônquios entre 15 a 21 dias. Este estudo permitiu a identificação de eventos normais que ocorrem durante o desenvolvimento do sistema respiratório de emas, importante modelo ainda não descrito. As informações geradas serão úteis para o diagnóstico de patologias que acometem este sistema orgânico, visando a melhoria dos sistemas de produção em cativeiro.(AU)

Porocarcinoma Ecrino / Ecrine Porocarcinoma

Resumen:El porocarcinoma ecrino es un tipo muy poco frecuente de cáncer de piel, originado en la porción epidérmica de las glándulas sudoríparas ecrinas. Representa no más del 0.01% de los tumores cutáneos. El 20% de los porocarcinomas ecrinos son recurrentes y el 20% producen metástasis a ganglios linfáticos. Se ha reportado escasos casos de metástasis a distancia. Tiene un índice de mortalidad del 67% de los pacientes con metástasis.El diagnóstico es basado en los hallazgos histopatológicos y los estudios complementarios de inmunohistoquímica, a veces necesarios para el diagnóstico diferencial con otros tipos más frecuentes de cáncer de piel.No existen pruebas de que este tipo de carcinoma responda a la quimioterapia ni la radioterapia. Se considera que el manejo principal debe ser la resección quirúrgica y la electroquimioterapia.

Abstract:Eccrine porocarcinoma is a rare type of skin cáncer arising from the intraepidermal portion of eccrine sweat glands, representing no more tan 0.01% of all cutaneous tumors. 20% of the Eccrine porocarcinoma will recur and 20% will metastasize to regional lymph nodes. Few cases of distant metastases has been reported . There is a mortality rate of 67% in patients with metastases. The diagnosis is primarily based on histopathologic findings and complementary immunohistochemistry for differential diagnosis mainly with more frequent skin cáncer.Neither chemotherapy nor radiation therapy has been proven to be of clinical benefit in treating this type of carcinoma. It is considered that the management should be based on surgical resection and electrochemotherapy.

New EMA real-time fluorescence PCR method for detection of alive Listeria monocytogenes in foods / 中国人兽共患病学报

A new EMA real-time fluorescence PCR method was developed to detect alive Listeria monocytogenes in foods.The specific primers and probe were designed based on the conserved inlA gene.The pretreatment conditions including EMA of different concentrations and irradiating times were optimized.The detection limit and inhibition rate to dead bacteria of this method were confirmed by using direct plating method.The detection specificity was evaluated by using 35 L.monocytogenes strains,25 non-L.monocytogenes strains and 92 non-Listeria strains.Simulation detection experiments were performed on 15 beverage samples and 15 cooked meat samples supplemented separately with inactivated L.monocytogenes,alive L.monocytogenes and Staphylococcus aureus.Results showed that the Ct of EMA real-time fluorescence PCR for alive L.monocytogenes was Ct=38.46-3.30 × log (R2=0.999).The detection limit was 55 cfu per reaction.Inhibition rate of DNA of inactivated strains was over 99.98％.The Ct of 35 L.monocytogenes strains were between 16.21 and 29.38,while 25 non-L.monocytogenes strains and 92 non-Listeria strains had Ct ＞35.The variation coefficient of CT was less than 5％ when the experiments were repeated.Results of 30 simulation samples were consistent with that by using standard method.The test time by using newly developed EMA real-time fluorescence PCR was shortened from 3-5 days to about 10 h.The newly developed EMA real-time fluorescence PCR method for alive L.monocytogenes is rapid,convenient,specific and sensitive and could be applyed in foods inspection.

Introduction to EMA guideline on therapeutic equivalence studies of generic and reformulated products that are locally applied, locally acting in gastrointestinal tract / 药物评价研究

EMA announced Guideline on equivalence studies for the demonstration of therapeutic equivalence for products that are locally applied,locally acting in the gastrointestinal tract as addendum to the guideline on the clinical requirements for locally applied,locally acting products containing known constituents (Draft) in March 2017,and proposed the general requirements for this equivalence study,introduced the requirements of equivalence studies for drugs acting different parts of the gastrointestinal tract,such as the mouth and/or throat,stomach,intestine and rectum,in detail,which focus on alternative methods of clinical trials-in vitro equivalence tests and PK bioequivalence studies.The guideline is introduced and it is expected to enlighten the trains of thought and methods for efficacy consistency evaluation of such generic and reformulated products in China.

Introduction to EMA guideline on therapeutic equivalence studies of generic and reformulated products that are locally applied, locally acting in gastrointestinal tract / 药物评价研究

EMA announced Guideline on equivalence studies for the demonstration of therapeutic equivalence for products that are locally applied,locally acting in the gastrointestinal tract as addendum to the guideline on the clinical requirements for locally applied,locally acting products containing known constituents (Draft) in March 2017,and proposed the general requirements for this equivalence study,introduced the requirements of equivalence studies for drugs acting different parts of the gastrointestinal tract,such as the mouth and/or throat,stomach,intestine and rectum,in detail,which focus on alternative methods of clinical trials-in vitro equivalence tests and PK bioequivalence studies.The guideline is introduced and it is expected to enlighten the trains of thought and methods for efficacy consistency evaluation of such generic and reformulated products in China.

Analgesic effect of angiotensin angiotensin Ⅱ type 2 receptor antagonist EMA401 on neuropathic pain in rats and its mechanism / 中国病理生理杂志

AIM:To explore whether angiotensin Ⅱtype 2 receptor antagonist EMA 401 decreases neuropathic pain and the expression of growth-associated protein-43 (GAP-43), protein kinase C (PKC) and calmodulin (CaM) in dorsal root ganglia (DRG) during chronic constriction injury (CCI) in rats.METHODS:SD rats were used to establish CCI model and randomly divided into 4 groups.The rats in model group were given equal volume of normal saline by intra-gastric administration .The rats in low dose ( LD) group were given 5 mg/kg EMA401 by intragastric administration .The rats in middle dose ( MD) group were given 10 mg/kg EMA401 by intragastric administration .The rats high dose ( HD) group were given 20 mg/kg EMA401 by intragastric administration .The rats in sham operation group received equal volume of normal saline by intragastric administration .Thermal withdrawal latency ( TWL ) and mechanical withdrawal threshold (MWT) were measured before operation and 7 d, 14 d and 28 d after CCI.After behavioral test, DRG of lumbar spinal was obtained from each group , and was used to determine Ca 2+concentration by o-cresolphthalein complexone microplating method, and the expression of GAP-43, PKC and CaM at mRNA and protein levels by Western blotting and RT-PCR.RE-SULTS:Compared with model group, EMA401 significantly increased the TWL and MWT (P <0.05).Meanwhile, EMA401 significantly reduced Ca 2+concentration and the expression of GAP-43, PKC and CaM at mRNA and protein levels in the DRG (P<0.05).CONCLUSION:EMA401 may attenuate neuropathic pain of CCI by inhibiting Ca 2+concentra-tion and the expression of GAP-43, PKC and CaM.

Frecuencia de anticuerpos anti-transglutaminasa y antiendomisio en pacientes con diabetes tipo 1 / Association of type 1 diabetes mellitus with celiac disease

Background: Type 1 diabetes mellitus and celiac disease share common genetic and immunological aspects and celiac disease is more common among type 1 diabetic patients. Aim: To determine the frequency of anti endomysial and anti transglutaminase antibodies among patients with type 1 diabetes. Material and Methods: Anti endomysialantibodies determined by indirect immunofluorescence an anti transglutaminase antibodies determined by ELISA were measured in 410 serum samples of patients with type 1 diabetes. Results: Seventy one samples (17 percent) had positive anti transglutaminase antibodies. Among these, 17 had also positive anti endomysial antibodies. In 11 of these 17 patients, the presence of celiac disease was confirmed. Conclusions: Among patients with type 1 diabetes mellitus, the frequency of celiac disease is three times higher than in the general population.

An analysis of clinical features of celiac disease patients in different ethnic / 中华内科杂志

Objective To summarize the clinical features of different racial patients with celiac disease (CD) and analyze the disease prevalence,diagnosis and treatment in Chinese population.Methods All the patients were diagnosed as CD and enrolled in Beijing United Family Hospital between January 2005 and July 2015.Clinical data including nationality,age,symptoms,endoscopic and pathological findings,outcome were collected and compared in patients from different countries.Results A total of 87 patients were enrolled including 63 Caucasians,18 Asian patients and 6 Middle East patients.The peak age of disease onset was 40-60 years old.Patients with typical symptoms such as chronic diarrhea and weight loss only accounted for 20.7％ (18/87) and 9.2％ (8/87) respectively.Some patients presented with nonspecific symptoms such as abdominal pain and bloating [32.2％ (28/87)],even constipation [5.7％ (5/87)].13.8％ (12/87) patients were previously diagnosed as irritable bowel syndrome.The incidence of abdominal pain,bloating,diarrhea and constipation between Asians and Caucasians had no statistical significance (P ＞ 0.05);but the proportions of weight loss,growth retardation,iron deficiency anemia and dermatitis herpetiformis in Asian group were significantly higher than that in Caucasian group (P ＜ 0.05).IgA type of anti-gliadin antibody (AGA),endomysium antibody (EMA) and tissue transglutaminase antibody (tTGA) were dominant autoimmune antibodies in patients with CD,which accounted for 58.6％ (51/87),44.8％ (39/87) and 36.8％ (32/87) respectively.The endoscopy showed that the lesion of CD was mainly located in small intestine,with reducing severity from the proximal to the distal small intestine.The lesions of duodenal bulb and descending duodenum appeared more significant in Asian group.Accordingly pathological intestinal atrophy and the degree of intraepithelial lymphocytosis were more severe in Asian patients.All 87 cases took the gluten-free diet (GFD).Eighty-one cases received serological follow up and 8 with endoscopic intestinal biopsy.The celiac disease antibodies in 47 patients turned negative from 6-9 months after GFD treatment,while 34 patients turned negative from 12-18 months after GFD.All patients reported disease remission to some extent.After 1 year GFD treatment,the pathology of endoscopic intestinal biopsy in 8 patients showed significant improvement of villous atrophy and lymphocyte infiltration.Conclusions CD patients with typical clinical manifestations are not the majority.Serological celiac disease antibodies (AGA,EMA and tTGA) have a high diagnostic value.GFD treatment is effective on majority of celiac patients.Clinical manifestations,endoscopy,intestinal pathology,and response to GFD in Chinese patients are not the same as Caucasians.Clinicians need to pay attention to the differential diagnosis.

Cholangiocarcinoma in an American Rhea (Rhea Americana araneipes) / Colangiocarcinoma em uma ema

Cholangiocarcinomas are neoplasms that originate from the bile duct epithelium. The present case described a cholangiocarcinoma in an adult female American Rhea (Rhea Americana araneipes) by means of gross, histopathology and immunohistochemistry. Irregular, firm, multifocal, yellow-white masses, measuring from 0.4 to 6cm in diameter were observed in both liver lobes. At the cut surface, multiple firm nodules filled with connective tissue were present. Microscopically, the neoplasia was composed of small, irregular, gland-like structures of neoplastic cells surrounded by connective tissue. The cells resembled epithelial cells of the hepatic biliary ducts. Neoplastic cells were positive for cytokeratin and negative for vimentin. This is the first report of a malignant fatal neoplasia in an American Rhea.

Colangiocarcinomas são neoplasias originárias do epitélio do ducto biliar. O presente caso descreve os achados macroscópicos, microscópicos e imuno-histoquímicos de um colangiocarcinoma em uma ema fêmea (Rhea americana araneipes). No fígado, massas irregulares, firmes, multifocais, de coloração amarelo-esbranquiçada, medindo de 0,4 a 6cm de diâmetro foram observadas em ambos os lobos. Ao corte, múltiplos nódulos firmes preenchidos por tecido conjuntivo foram observados. Microscopicamente, a neoplasia era composta de células pequenas, irregulares, semelhantes às células do epitélio biliar, que formavam estruturas glandulares. A imuno-histoquímica foi positiva para citoqueratina e negativa para vimentina. Este trabalho constitui o primeiro relato de uma neoplasia maligna fatal em uma ema.

Biological characteristics of lysostaphin-resistant Staphylococcus aureus variants induced by recombinant lysostaphin in vit ro / 中国感染与化疗杂志

Objective To investigate the phenotypic and genetic characteristics of the lysostaphin‐resistant Staphylococcus aureus variants induced by recombinant lysostaphin in vitro .Methods Three clinical isolates of S . aureus ,including two resistant to methicillin (MRSA ) and one susceptible to methicillin (MSSA ) were induced by treatment with sub‐MIC of recombinant lysostaphin via one‐step selection in vitro .Susceptibility of the variants to antibiotics were determined and compared with their parental strains .The full length of femABX genes was amplified by polymerase chain reaction and sequenced to identify the potential mutation sites in these genes .The growth‐curve in liquid medium and virulence in a mouse systemic infection model of both parental and variant strains were observed . Results The frequency of lysostaphin resistance in S . aureus was between 10-4 to 10-8 following induction by lysostaphin . Resistance to lysostaphin was associated with a significant decrease in growth rate in vitro and virulence in vivo ,as well as increased susceptibility toβ‐lactams evidenced by the M IC of β‐lactams against the variants as low as 1/4 000 to 1/2 of the M IC against their parental strains . Sequencing of f emA BX genes showed mutation in femA gene in both variants ,which resulted in a premature termination codon .Conclusions Resistance of S . aureus to lysostaphin may develop following induction by recombinant lysostaphin in vitro . The lysostaphin‐resistant S . aureus variants are characteristic of lower growth rate , decreased virulence ,and higher susceptibility to β‐lactams .

Hyperthyroid-associated EMA syndrome:four cases report and review of literature / 中华内分泌代谢杂志

[Summary] Four patients with hyperthyroid-associated exophthalmos, myxedema, acropachy ( EMA ) syndrome, including three male patients and one female patient were diagnosed with Graves′diseases and treated by 131 I therapy. Complaints of thyrotoxicosis were presented at the onset. Tibia myxedema and acropathy appeared, and eye symptoms aggravated in two patients after anti-thyroid drug therapy and 131 I therapy. Four cases were all given clobetasol propionate, miconazole nitrate, neomycin sulfate and urea cream alone or in combination with compound betamethasone local injection treatment, and three cases were given low-dose oral prednisone treatment. Complaints of tibia myxedema and eye symptoms were significantly improved after the treatment. Therefore, we should be wary of the occurrence of hyperthyroid-associated EMA syndrome after 131 I therapy. Corticosteroid might be the effective therapy for myxedema and eye symptoms of EMA syndrome.

Primary pulmonary synovial sarcoma: a rare case report.

Primary lung sarcoma is an extremely rare tumor, accounting for less than 0.5% of all lung tumors. Histological subtypes are differentiated on the basis of immunohistochemical markers, such as vimentin, desmin, actin, CD99, and epithelial membrane antigen. A 50-year-old male presented with progressively increasing shortness of breath with cough for 2 months. On Contrast Enhanced Computed Tomography (CECT) of thorax a large heterogeneous mass with multiple areas of necrosis, occupying almost whole of left hemithorax was seen. CT-guided Fine Needle Aspiration Cytology (FNAC) revealed spindle cell neoplasm. Histopathological examination revealed a spindle cell sarcoma. On immunohistochemistry the tumor cells expressed both epithelial membrane antigen and vimentin. Hence, final impression from immunohistochemistry was primary monophasic synovial sarcoma of lung.

Malignant Mesothelioma vs. Reactive Mesothelial Proliferations: Immunohistochemical Profile.

Aims: To examine the distribution of immunohistochemical markers GLUT-1, EMA (membrane epithelial antigen) and Ki-67 in benign and malignant mesothelial lesions. Thus, the sensitivity, specificity, positive and negative predictive value of these markers, used alone or in conjunction, was established. Study Design: Observational, retro-prospective and non-randomized study. Place and Duration of Study: Department of Pathology, Center for Medical Education and Clinical Research "Norberto Quirno" (CEMIC), between 2004 and 2011. Methodology: A total of 53 cases diagnosed as mesothelioma (n=15) or reactive mesothelial hyperplasia (n=38) were selected. Routine techniques using hematoxylineosin and immunostaining with EMA, GLUT-1, and Mib-1 were performed. Results: Mesotheliomas cohort was immunoreactive for GLUT-1 in 11/15 (73%) cases, and for EMA in 13/15 (87%) cases. The group of reactive lesions was positive for GLUT- 1 in 2/38 cases (5%), and positive for EMA in 7/38 (18%) cases. The median proliferation rate was 1% in benign lesions and 3% in mesotheliomas. The sensitivity and specificity for EMA was 87% and 82% respectively, with a positive predictive value of 65% and a negative predictive value of 94%. The sensitivity and specificity for GLUT-1 was 73% and 95% respectively, with a positive predictive value of 85% and a negative predictive value of 90%. Conclusion: EMA and GLUT-1 are sensitive and specific markers that express more frequently in mesothelioma than in benign mesothelial lesions with higher specificity in the case of GLUT-1 for the detection of malignant proliferations. In a mesothelial proliferation without invasion criteria, EMA and GLUT-1, including histopathology, may be sensitive and specific markers to define malignancy. Thus, a morphologically doubtful mesothelial proliferation with positive staining (diffuse and intense), for these antibodies could be a mesothelioma. However, the evidence of underlying tissue infiltration by mesothelial cells currently remains the gold standard for diagnosis of mesothelioma. Both markers should be included in the immunohistochemical panel to distinguish benign from malignant mesothelial lesions.

Neuropatía autonómica diabética cardiovascular / Diabetic autonomic cardiovascular neuropathy

La neuropatía autonómica diabética cardiovascular es un trastorno en el cual una alteración en la regulación del sistema nervioso cardiovascular, por parte del sistema nervioso autónomo, desemboca en una constelación de síntomas, que pueden ir desde intolerancia al ejercicio hasta muerte súbita. Si bien no se conoce su prevalencia exacta, se estima que es alta en pacientes diabéticos, particularmente en aquellos con diabetes de larga data y con presencia de otras comorbilidades. Su reconocimiento temprano puede facilitar el manejo de estos pacientes y a su vez disminuir los costos asociados a pruebas e intervenciones innecesarias con el objetivo de evitar complicaciones asociadas con la enfermedad.

Cardiac autonomic diabetic neuropathy is a condition in which impairment of the autonomic control of the cardiovascular system leads to a myriad of symptoms, ranging from mild exercise intolerance to sudden cardiac death. Even though its exact prevalence is unknown, it is believed that it is highly prevalent in patients with long-standing diabetes, particularly those who have other pathologic conditions. Early detection is expected to have a positive impact in patient treatment, lowering costs associated with unnecessary tests and treatments, while at the same time avoiding disease-related complications.

Macroscopia e topografia do aparelho digestório de emas (Rhea americana americana) / Gross morphology and topography of the digestive apparatus in rheas (Rhea americana americana)

As emas são aves que pertencem ao grupo das ratitas e juntamente com os avestruzes e emus, são as maiores aves vivas na atualidade. Neste trabalho estudou-se os aspectos macroscópicos do aparelho digestório de emas com o intuito de fornecer informações importantes ao estudo dos hábitos alimentares dessas aves, bem como de sua anatomia. Foram utilizados vinte animais jovens com idade entre dois e seis meses obtidos do Centro de Multiplicação de Animais Silvestres (Cemas), registrado com criador científico sob o nº 1478912. Após dissecação verificou-se que a língua era pequena, disposta no assoalho da cavidade oral, possui forma rombóide e estava inserida pela sua base por um frênulo. O esôfago era um tubo retilíneo de aspecto elástico com fibras longitudinais, sem dilatação, o que confere a ausência do papo. O proventrículo gástrico apresentava formato fusiforme. O ventrículo gástrico possuía formato ligeiramente oval, quando repleto, internamente era recoberto por uma cutícula gástrica espessa. O intestino delgado era formado por três regiões distintas: duodeno, jejuno e íleo. O duodeno possuía coloração cinza claro e apresentava-se curvado em forma de "U". O jejuno era longo e formado por várias alças curtas dispostas uma sobre a outra e possuía coloração verde escuro. O íleo era de cor cinza e continuo com o jejuno. Na linha ventral ao reto e cloaca, este se estendia em sentido cranial, dorsalmente ao duodeno ascendente. O intestino grosso era formado por dois cecos, um direito e um esquerdo, e o cólon-reto contínuo com o íleo e a cloaca. As estruturas que compõem o aparelho digestório de ema assemelham-se com o que preconiza a literatura, com relação à forma e topografia para a maioria das aves, contudo os cecos são bem desenvolvidos e bastante dilatados nas emas.

Rheas are birds belonging to the ratites group and, among ostriches and emus, are the largest birds currently alive. In this work we studied the macroscopic aspects of rheas' digestive tract in order to provide important information to a better understanding of these birds' eating habits as well their anatomy. Twenty young animals aging between two and six months from the Centre for Wild Animals Multiplication (Cemas, scientific breeding license form Ibama no.1478912) were used. After dissection it was observed that their tongue was small and presented a rhomboid form, being disposed on the oral cavity floor, and inserted in its base by a frenulum. The esophagus was a rectilinear tube with elastic aspect and longitudinal elastic fibers, without dilation, which gives it an absence of crop. The proventriculus presented a fusiform form and the gastric ventricle showed and slightly oval form when filled, and was internally coated with a thick gastric cuticle. The small intestine was composed of three distinct regions: duodenum, jejunum and ileum. The duodenum had a light gray color and showed a "U" curved shaped. The jejunum was dark green, long and composed of several short loops arranged above each other. The ileum had a gray color and was connected with the jejunum. In ventral line to the rectum and cloaca, the ileum extended cranially, dorsally to the ascending duodenum. The large intestine was composed of two caeca, one right and one left, and colon-rectum and ileum were continuous with the cloaca. The structures of the rhea digestive tract resemble those described in the literature regarding to its shape and topography, even though rhea's caeca are well developed and relatively long.