Genetic and phenotypic analysis of MYO15A rare variants associated with autosomal recessive hearing loss / 临床耳鼻咽喉头颈外科杂志

Objective:To analyze the phenotype and genotype characteristics of autosomal recessive hearing loss caused by MYO15A gene variants, and to provide genetic diagnosis and genetic counseling for patients and their families. Methods:Identification of MYO15A gene variants by next generation sequencing in two sporadic cases of hearing loss at Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. The sequence variants were verified by Sanger sequencing.The pathogenicity of these variants was determined according to the American College of Medical Genetics and Genomics（ACMG） variant classification guidelines, in conjuction with clinical data. Results:The probands of the two families have bilateral,severe or complete hearing loss.Four variants of MYO15A were identified, including one pathogenic variant that has been reported, two likely pathogenic variants,and one splicing variant of uncertain significance. Patient I carries c. 3524dupA（p. Ser1176Valfs*14）, a reported pathogenic variant, and a splicing variant c. 10082+3G>A of uncertain significance according to the ACMG guidelines. Patient I was treated with bilateral hearing aids with satisfactory effect, demonstrated average hearing thresholds of 37.5 dB in the right ear and 33.75 dB in the left ear. Patient Ⅱ carries c. 7441_7442del（p. Leu2481Glufs*86） and c. 10250_10252del（p. Ser3417del）,a pair of as likely pathogenic variants according to the ACMG guidelines. Patient Ⅱ, who underwent right cochlear implantation eight years ago, achieved scores of 9 on the Categorical Auditory Performance-Ⅱ（CAP-Ⅱ） and 5 on the Speech Intelligibility Rating（SIR）. Conclusion:This study's discovery of the rare c. 7441_7442del variant and the splicing variant c. 10082+3G>A in the MYO15A gene is closely associated with autosomal recessive hearing loss, expanding the MYO15A variant spectrum. Additionally, the pathogenicity assessment of the splicing variant facilitates classification of splicing variations.

Los desencadenantes reflejos en la epilepsia mioclónica juvenil / Reflex triggers in juvenile myoclonic epilepsy

Resumen Introducción : La epilepsia mioclónica juvenil (EMJ) es un síndrome epiléptico de inicio en la infancia y ado lescencia con mioclonías, convulsiones tónico-clónicas generalizadas y ausencias. Los estímulos reflejos como la sensibilidad a la luz o fotosensibilidad, la apertura y cierre palpebral y la inducción por praxias producen descargas epileptiformes y crisis. Estos desencadenan tes reflejos no son todos sistemáticamente estudiados. Objetivo : Examinar los rasgos reflejos en pacientes con EMJ. Métodos : Se evaluaron en forma consecutiva 100 adolescentes y adultos con EMJ que recibían diferentes tratamientos anticrisis. Se realizó un electroencefalogra ma standard con un protocolo de estimulación luminosa intermitente (ELI) y otro para la evaluación de las pra xias a través de una actividad neurocognitiva (ANC). El análisis estadístico fue descriptivo y de correlación. Se consideró significativa una p > 0.05. Resultados : La edad actual fue de 28+/-11 (14-67). Las crisis comenzaron a los 15 años +/-3 (Rango 8-25 años). EL 58% presentaron mioclonías y convulsiones tónico clónicas generalizadas. El 50% recibían ácido valproico y el 31% continuaban con crisis. Descargas epileptiformes en reposo 20%; hiperventilación 30%; apertura y cierre palpebral 12%; respuesta fotoparoxística en la ELI 40%; ANC 23%. Mayor porcentaje de descargas y demora en la realización de la ANC en los que presentaban crisis. El ácido valproico comparado con los otros fármacos no demostró superioridad en el control de las crisis. Conclusiones : Estos hallazgos confirman la importan cia del estudio de los rasgos reflejos para el diagnóstico, seguimiento y el control terapéutico.

Abstract Introduction : Juvenile myoclonic epilepsy (JME) is an epileptic syndrome with onset in childhood and adolescence with myoclonus, absences, and generalized tonic-clonic seizures. Reflex stimuli such as sensitivity to light or photosensitivity, eyelid opening and closing, and praxis induction produce epileptiform discharges and seizures. These reflex triggers are not all system atically studied. Objective : Examine reflex features in patients with JME. Methods : One hundred adolescents and adults with JME who received different anti-seizure treatments were evaluated consecutively. A standard electroen cephalogram was performed with an intermittent light stimulation (SLI) protocol and another for the evaluation of praxias through neurocognitive activity (CNA). The statistical analysis was descriptive and of correlation with a p > 0.05. Results : Current age was 28+/-11 (14-67). The seizure began at 15 years +/-3 (Range 8-25 years). They pre sented myoclonus and generalized tonic-clonic seizures in 58%. 50% received valproic acid and 31% continued with seizures. Epileptiform discharges at rest 20%; hy perventilation 30%; eyelid opening and closing 12%; photoparoxysmal response in SLI 40%; CNA 23%. Higher percentage of discharges and delay in performing CNA in those who presented seizures. Valproic acid com pared to other drugs did not demonstrate superiority in seizure control. Conclusions : These findings confirm the importance of studying reflex traits for diagnosis, follow-up, and therapeutic control.

OBSERVATIONAL PROSPECTIVE STUDY OF DIFFERENT RECONSTRUCTIVE SURGERY IN ORAL CAVITY CARCINOMA

OBJECTIVES & AIMS:• To evaluate the outcome of different Reconstructive surgery in oral cavity carcinoma• To determine the factors which increase the complication in post op reconstructive surgery(like – diabetes, hypertension, smoking etc.)• The effect of flap transfer on complication or on post op rehabilitation of patients in oralcavity carcinoma.MATERIALS AND METHODS: This is a prospective study conducted at GCS hospital,Ahmedabad between oct. 2021 to June 2022. Sample size is 40 patients with case of oral cavitycarcinoma, out of which some cases underwent for PMMC Flap, Radial forearm free flap, ALTfree flap, fibula flap, forehead rotational flap, deltopectoral flap and local flap.CONCLUSION:Risks have not increased complications in PMMC or Free flap group in our study. Various otherstudies have similar results however a larger patient pool may be needed to assess them. ThePMMC flap is more favorable for patients with possibly lethal pre-op morbidities, when a longoperation is not advisable and a small defect is expected as compared to the longer operationduration of ALT free flap & Radial free flap.Though the flap related complications & donor site related complications are more with foreheadrotational flap as compared to PMMC. ALT & Radial forearm free flap, statistically there is nosignificant difference. Also, in the functional post-op outcomes there is minimally statisticallysignificant difference with PMMC flap, ALT free flap or Radial free flap, local flaps and otherreconstructive surgery.

HISTOLOGICAL VARIANTS OF BLADDER TUMORS : DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC IMPLICATIONS – A CASE SERIES

Bladder cancer is one of the leading malignancies in the world associated with signi?cant morbidity and mortality. About 80% of a bladder cancer is urothelial variant, remaining 20% will have a divergent histological presentation. The pathophysiological study of these variants has recently increased because the therapeutic approach is not uniform for all variants. These variants have important diagnostic, prognostic and therapeutic implications. A molecular and genetic study of these variants will allow them to be better de?ned. Here we present four cases of Histological variants of bladder tumors with varying presentations in the department of urology, Madurai medical college, which is studied over the period of one year (2022-2023).

Effect of Thymoquinone on skeletal muscle regeneration via assessment of Pax-7 and Myo-D expression in the DMBA-treated hamster pouch / Efeito da Timoquinona na regeneração muscular esquelética através da avaliação da expressão das proteínas Pax-7 e Myo-D em bolsa jugal de hamsters tratados com DMBA

Objective: Pax-7 and Myo-D regulate satellite cells' activation and differentiation, thus muscle regeneration following damage. This research aimed to investigate the effect of Thymoquinone (TQ) on skeletal muscle regeneration following 7,12-dimethylbenz-(a)-anthracene (DMBA)-induced injury in the hamster buccal pouch via immunohistochemical assessment of Pax-7 and Myo-D expression. Material and Methods: 65 male golden Syrian hamsters were divided into 3 groups: Group 1: (n=5) received no treatment. Group 2: (n=20) served as a positive control. The left buccal pouches were painted with the carcinogen 3/week/ 6weeks. Group 3: (n=40) were subdivided into two equal sub-groups as follows: Group 3a: (n=20) were given one i.p. TQ injection. Group 3b: (n=20) were given two i.p. TQ injections. Five animals from each group (2 and 3) were euthanized at 24, 48 hrs, one, and two weeks after the last injection. A blood sample (2 ml) was withdrawn for assessment of TNF-α levels in serum. Serial sections of the pouches were examined histologically (H&E), and immunohistochemically (IHC) for the detection of Pax-7 and Myo-D proteins. Results: double i.p injections of TQ resulted in a significant elevation in the level of TNF-α from the second-day post-injection with a progressive formation of the muscle fibers (MFs) and mononuclear cells (MNCs) around the deeper blood vessels. At 14 days, no statistically significant difference was found between this group and group '2', while the difference remained significant compared to groups '1' and '3a'. The muscle fibers were more mature and compact. IHC results showed positive expression of the perivascular mononuclear cells (MNCs) to both Pax-7 and Myo-D with positive reactivity of the peripheral nuclei of muscle fibers to Pax-7 compared to the negative reaction in the positive control group. Conclusion: early and two TQ injections had a promising effect on the induction of striated muscle regeneration, mainly by non-myogenic stem cells (AU)

Objetivo: Pax-7 e Myo-D regulam a ativação e diferenciação de células satélites durante a regeneração muscular pós-trauma. Assim, objetivamos investigar o efeito da timoquinona (TQ) na regeneração muscular esquelética após injúria causada por 7,12 dimetilbenzantraceno (DMBA) em bolsa jugal de hamsters, através da análise imuno-histoquímica de Pax-7 e Myo-D. Material e Métodos: 65 hamsters-sírios machos foram divididos em 3 grupos: Grupo 1: (n=5) controle negativo, sem tratamento. Grupo 2: (n=20) controle positivo. A bolsa jugal do lado esquerdo recebeu aplicação do DMBA por 3 e 6 semanas. Grupo 3: (n=40) receberam aplicação de DMBA e foram então subdivididos em: Grupo 3a: (n=20) que recebeu 1 injeção intraperitoneal (ip) de TQ e Grupo 3b: (n=20) que recebeu duas injeções ip de TQ. Cinco animais dos grupos 2 e 3 foram eutanasiados em 24 horas, 48 horas, 7 dias e 14 dias após a administração de DMBA e da última injeção de TQ. Amostras de sangue (2 ml) foram coletadas para avaliação dos níveis séricos de TNF-α. Cortes seriados da bolsa jugal dos animais foram analisados histologicamente (H&E), e através de imunohistoquimica (IHC) para avaliação das proteínas Pax-7 e Myo-D. Resultados: duas injeções ip de TQ aumentaram os níveis séricos TNF-α à partir do segundo dia pós-administração com formação progressiva de fibras musculares (MFs) e células mononucleares (MNCs) ao redor dos vasos sanguíneos. No dia 14, não houve diferença estatística entre o grupo 3b e o grupo 2, enquanto a diferença permaneceu entre o grupo 1 e 3a. As MFs apresentavam-se mais maduras e compactas. A IHC mostrou expressão de Pax-7 e Myo-D nas MNCs ao redor dos vasos, e houve expressão nuclear de Pax-7 nas MFs no grupo 2. Conclusão: ambos regimes de administração do TQ, 1 ou 2 aplicações ip, apresentaram efeito promissor na indução da regeneração muscular esquelética, principalmente nas células não-miogênicas.(AU)

Adult hemophagocytic syndrome with mutations in UNC13D and MYO5A genes: a case report and literature review / 中国综合临床

Objective:To explore the pathogenesis of primary hemophagocytic syndrome with UNC13D and MYO5A gene mutations.Methods:A case of adult hemophagocytic syndrome with gene mutation of UNC13D and MYO5A admitted to The 940th Hospital of the Joint Logistic Support Force of the PLA on January 28, 2022 was retrospectively analyzed in terms of laboratory examination, gene atlas of its close relatives and prognosis, and related literature was reviewed.Results:The patient was finally diagnosed with primary hemophagocytic syndrome, and chemotherapy was performed twice with hemophagocytic lymphohistiocytosis(HLH)-2004 regimen. The HLA matching of his cytoplasm was semi-compatible. Considering that his cytoplasm carried blood-macrophage related genes, it was not suitable to be selected as a donor, and there were no other suitable relatives. He was transferred to another hospital for allogeneic hematopoietic stem cell transplantation, but failed to receive allogeneic hematopoietic stem cell transplantation during telephone follow-up, and died.Conclusion:The gene mutation of primary hemophagocytic syndrome is the gold standard for the diagnosis of primary HLH. There may be dual gene inheritance pattern in primary HLH, and the combination of immune disorder caused by viral infection and genetic factors may lead to the pathogenesis of primary HLH.

Efficacy of myo-inositol in improving pregnancy rate and regulation of menstrual cycle for patients with polycystic ovarian syndrome: A systematic review and meta-analysis

Background@#Polycystic ovarian syndrome (PCOS) is a common, reproductive endocrinopathy associated with ovarian dysfunction, cardiovascular disorders, obesity, and infertility. Myo-inositol is a novel treatment for women with PCOS that claimed to have improved fertility rate in this population. This systematic review and meta-analysis examined the effect of myo-inositol on pregnancy rate, menstrual cycle, and adverse effects from randomized controlled trials (RCTs). @*Methods@#RCTs that evaluated the efficacy of myo-inositol in improving pregnancy rate and regulation of menstrual cycle in women with PCOS. Electronic databases were searched and studies published up to October 24, 2021 were included in the systematic review and meta-analysis. Study selection and assessment of quality were conducted independently by two review authors. @*Results@#Seven studies with 729 patients treated with myo-inositol and 677 patients treated with placebo and/or metformin were included in the analysis. The research groups did not diverge significantly in terms of basic characteristics, such as age, adnexal or uterine pathology, body mass index, and duration of infertility. In the myo-inositol group, regulation of the normal menstrual cycle is at 20%, significantly higher than the metformin group at 12%, (p<0.001). However, there is no significant difference in the pregnancy rate between myoinositol and placebo (p=0.42) and/or metformin (p=0.17). @*Conclusion@#This systematic review and meta-analysis showed that myo-inositol can be an alternative treatment for PCOS in terms of regulation of menses and may improve the success of spontaneous pregnancies. However, additional randomized, double-blind controlled trials with larger sample sizes, low heterogeneity, and uniform inclusion criteria are recommended to establish the effects of myo-inositol on PCOS treatment and pregnancy rate.

Whole-Exome Sequencing Reveals Pediatric Rare Syndromic Hearing Loss / 罕见病研究

  Objective  To discuss the significance of genetic diagnosis of children with syndromic hearing loss by using whole-exome sequencing.  Methods  The clinical data of 34 children with sensorineural hearing loss were collected and the whole exons of genome of the children and their parents were sequenced and analyzed.  Results  Genetic causative gene and mutations have been identified in 19 children, including 4 genes (HARS2, USH2A, GATA3, MITF) related to rare syndromic hearing loss. Fifteen children were diagnosed with non-syndromic hearing loss related gene, including 8 cases with GJB2 mutation, 5 cases with SLC26A4 mutation and 2 cases with MYO15A mutation. Mutations of c.435_437del(p.K147del) and c.1403G > C (p.G468A) in gene HARS2, c.11389+1del in gene USH2A, c.1327delA(p.M443Wfs*33) in gene GATA3, c.627C > A(p.C209X) in gene MITF and c.8033_8057delinsG(p.N2678_D2686delinsS) in gene MYO15A were first reported.  Conclusions  Whole-exome sequencing helps the accurate diagnosis of causes of hearing loss, especially for the rare syndromic hearing loss with atypical clinical manifestations. Information from genetic testing may highlight further recommended exams of structure and functions of related organs.

Femoral Neck Non-union Treated using Compression Screw with or without Gluteus Medius Trochanteric Flap: A Case Series of Ten patients

@#Non-union is a challenging complication following a femoral neck fracture. Inability to achieve anatomical reduction and compression over the fracture leads to non-union. We reported a 10-case series of femoral neck non-union treated with sliding compression screw and anti-rotational screw with or without gluteus medius local trochanteric flap. When compression could not be achieved and a gap was present over the non-union site, a gluteus medius trochanteric flap was used to enhance the union. Surgeries were performed as a single-stage procedure through the Watson Jones approach. The initial implants were removed, followed by fracture reduction, during which the varus deformity was corrected, and the neck length was preserved as much as possible. Patients were advised for strict non-weight bearing until the presence of trabecular bone crossing the fracture on the radiographs. Union was achieved at three months in all cases. Patients undergoing surgery without trochanteric flap had normal abduction strength, and the neck length was maintained. All cases had no significant loss of function. Patients with trochanteric myo-osseous flap had neck shortening with weak abductors with MRC grade 4. Two out of 10 cases developed avascular necrosis of the femoral head before intervention. One case progressed to collapse of the femoral head requiring implant removal. This and the femoral neck shortening, caused this patient to have weak abductors and a positive Trendelenburg gait. We observed that delayed surgery leads to neck shortening and fracture gap requiring trochanteric myo-osseous flap to achieve union.

Expression of 1L-myo-Inositol -1-Phosphate Synthase (EC 5.5.1.4) is Deregulated in the Cerebellum of Curly Tail Mutant Mice

Previous research, defining spatial control of inositol phosphate biosynthesis in the developing brain of CBA (normal) and CT [curly tail (ct-CT) and straight tail (st-CT)] mutant mice implicated a role for 1l-myo-inositol 1-phosphate synthase (MIP) in normal functioning of the central nervous system. Biochemical research indicated that MIP enzymatic activity, conversion of glucose 6-phosphate into inositol phosphate, is highest in the cerebellum of ct-CT and lowest in st-CT, when compared to that of CBA mice.Here, we utilized microscopic and biochemical investigations to analyze and extend previous findings of MIP expression in the cerebellum. Results of this research indicated that MIP expression correlates, well, with its enzymatic activity in the cerebellum of CBA and CT mutantmice. Statistical analyses of fluorescent micrographs detected a significant difference in fluorescence intensity between MIP from ct-CT, st-CT, and CBA mice.These data support vitallinks between inositol phosphate biosynthesis, MIP expression, and normal functioning of the cerebellum. Moreover, published data, identifying significant behavioral differences in the CT mutant, as well as data linking motor and non-motor cerebellar functions to abnormal levels of inositol, support the conclusion that aspects of normal cerebellar functions require temporal and spatial control of inositol phosphate biosynthesis, MIP expression.

Application of Polymerase Chain ReactionRestriction Fragment Length Polymorphism (PCRRFLP) Technique in the Analysis of MYO1H Single Nucleotide Polymorphism in Malay Mandibular Prognathism Patients

@#Genetic studies have reported the association between polymorphism in MYO1H with mandibular prognathism. MYO1H is found in skeletal muscle sarcomeres and is expressed in the mandibular jaw cartilage signifying its importance during craniofacial development. This study aimed to characterise the genotype and allele of MYO1H single nucleotide polymorphism (SNP) (rs3825393) and to associate the SNP with mandibular prognathism in Class III skeletal malocclusion. This was a casecontrol study, which involved 57 Malay subjects with 30 Class I (control) and 27 Class III skeletal base patients (case). Cephalometric measurements were taken prior to collection of saliva samples. MYO1H SNP (rs3825383) was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Chi-square (χ2 ) test was used to compare genotype and allele frequencies between the groups while Hardy-Weinberg Equilibrium (HWE) was applied to assess distribution of genotype frequency in both classes. MYO1H SNP (rs3825393) did not yield significant association with mandibular prognathism with p = 0.33; OR = 0.66; 95% CI = 0.289~1.518, that was reflected by no significant difference in allele (p > 0.05) and genotype (p > 0.05) frequency between control and study group. Nevertheless, AA genotype depicted the highest frequency in both groups. The genotype distribution in both groups was in concordance with HWE (p > 0.05). Our data showed no association of MYO1H SNP (rs3825393) with mandibular prognathism. Interestingly, we observed Allele A representing the major allele in Malay population. Presence of MYO1H SNP (rs3825393) was detected in samples analysed. Larger number of samples is required to confirm the involvement of MYO1H polymorphisms in mandibular prognathism.

A comparative study of combination of Myo-inositol and D-chiro-inositol versus Metformin in the management of polycystic ovary syndrome in obese women with infertility

Background: Polycystic ovary syndrome (PCOS) is a symptom complex associated with increased amounts of circulating androgens in females, increased insulin resistance and obesity. The drugs, Myo-inositol, D-chiro-inositol and Metformin, which are insulin sensitizers, are very helpful in taking care of one of the key components of PCOS that is insulin resistance. This study was done to compare the effects of combination of Myo-inositol and D-chiro-inositol with the use of metformin on clinical and biochemical profile in PCOS.Methods: A prospective, randomized, comparative study was conducted on 200 patients. The patients were randomly assigned into the two groups of 100 each. Group A receiving Tab. Myoinositol 550mg twice daily and Tab. D-chiro-inositol 13.8mg twice daily and Group B receiving Tab. Metformin 500mg thrice daily. The patients were assessed by menstrual cycle regulation, hirsutism score (Ferriman Gallwey), fasting and post prandial glucose and insulin levels, serum DHEA levels, serum free testosterone levels and fasting day 3 serum LH and FSH ratio.Results: In both the groups there was significant improvement in all the above mentioned parameters, however the group with Combination of Myo-inositol and D-chiro-inositol had statistically significant improvement over the Metformin group.Conclusions: Combination of Myo-inositol and D-chiro-inositol and use of metformin, significantly improved insulin sensitivity in PCOS women. But combination of Myo-inositol and D-chiro-inositol was effective in controlling the hormonal profiles (LH/FSH ration and free testosterone) when compared to Metformin.

Thoraco-Acromial Artery : A Cadaveric Study Of Its Pedicle And Branches

Background of study- A detailed knowledge of variations in the origin and branching pattern of Thoraco-acromial artery(TAA) is important during various reconstructive and microvascular surgeries. Materials and methods- Hundred formalin xed specimens were studied at Government Medical College, Kozhikode, Kerala, India over a period of four years. Results- Normal quadrifurcation pattern was observed in majority of specimens (84%). The division of TAA into two trunks was seen in 9% followed by ramication into multiple branches in 4% specimens. Some specimens showed trifurcation (3%). Conclusion- In this scenario of increasing reconstructive surgeries, a thorough knowledge on the anatomical variations of TAA will be helpful to surgeons as this artery provides vascular supply to Pectoralis Major Myo-Cutaneous ap.

Analysis of MYO7A gene mutation in a family with non-syndromic autosomal recessive deafness / 中华医学遗传学杂志

Objective@#To explore the genetic basis for a family with non-syndromic autosomal recessive deafness.@*Methods@#The proband and her parents were subjected to physical and audiological examinations. With genomic DNA extracted from peripheral blood samples, next-generation sequencing was carried out using a panel for deafness genes. Suspected mutation was validated by Sanger sequencing and qPCR analysis of her parents.@*Results@#The proband presented bilateral severe sensorineural hearing loss at three days after birth. Her auditory threshold was 110-120 dBnHL but with absence of vestibular and retinal symptoms. Her brother also had deafness but her parents were normal. No abnormality was found upon physical examination of her family members, while audiological examination showed no middle ear or retrocochlear diseases. Next-generation sequencing identified compound heterozygous mutations of the MYO7A gene, including a previously known c. 462C>A (p. Cys154Ter) and a novel EX43_46 Del, which were respectively derived from her mother and father.@*Conclusion@#The compound heterozygous mutations of the MYO7A gene probably underlie the disease in this family. Our findings has enriched the mutation spectrum for non-syndromic autosomal recessive deafness 2.

Efficacy of Transcutaneous Electrical Nerve Stimulation (TENS) and Pharmacotherapies in Myofacial Pain: A Randomised Study

Background Temporomandibular disorder (TMD) is a collective term for the disorders involving the temporomandibular joint, the soft-tissue structures within the joint and the muscles of mastication. Myofascial pain is the most common type of painful TMD, characterised by pain in the muscles of mastication, frequently along with muscle dysfunction and tightness. Objectives To evaluate and compare the effectiveness of transcutaneous electrical nerve stimulation (TENS) with pharmacotherapy in the management of myofacial pain. Methodology A total of 40 patients with myofacial pain are divided into two groups, in which 20 patients (Group A) were treated with pharmacotherapy and other 20 patients (Group B) were treated with TENS. Results In Group B, all the patients were responded well for therapy, and there was significant reduction in myofacial pain as compared with patients in Group A. Conclusion Our study revealed a positive result towards TENS therapy and concluded that it can be given as first line of therapy.

Risk Assessment of "Other Substances" – Inositol

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating the addition of “other substances” to food supplements and other foods. "Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/ or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. In this series of risk assessments of "other substances", VKM has not evaluated any potential beneficial effects from these substances, only possible adverse effects. The present risk assessment is based on previous risk assessments of inositol and articles retrieved from a literature search. According to information from NFSA, inositol is an ingredient in energy drinks sold in Norway. NFSA has requested a risk assessment of 10 mg/100 ml inositol in energy drinks. Drinking patterns reflecting a high acute intake, a mean chronic intake and a high chronic intake were assessed. Inositol (CAS no. 6917-35-7) is a sugar alcohol. Among the nine possible stereoisomers, myo inositol (CAS no. 87-89-8) is the most abundant. The name inositol is frequently used as a synonym for myo -inositol. Inositol occurs naturally in all organisms including humans, and is an important component in all human cells. Inositol-containing lipids and phosphates are required for various structural and functional processes, including membrane formation, signalling, membrane trafficking and osmoregulation. Endogenous production of inositol in humans amounts to about 4 g/day (about 57 mg/kg bw per day in a 70 kg adult) (EFSA, 2014). The total dietary intake of inositol in adults is estimated to range between 500 to 1000 mg/day (about 7-14 mg/kg bw per day). Inositol added to energy drinks in Norway denotes the compound myo -inositol, according to information from NFSA. M yo -inositol is a water-soluble compound naturally occurring in the cells of all living organisms including humans, animals, plants and microorganisms. Certain plant (fruits and vegetables) and foods from animals contain inositol, and seeds of cereals and legumes show high levels of the inositol storage form, phytic acid (inositol hexaphosphate). With regard to hazard identification and characterisation of inositol, most of the adverse effects observed in several human studies were related to gastrointestinal symptoms such as nausea, flatulence, loose stools and diarrhoea. Drinking patterns reflecting a high acute intake, a mean chronic intake and a high chronic intake were assessed for energy drinks containing 10 mg inositol per 100 ml, for the age groups children (3 to <10 years and 10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years). For the high acute drinking pattern, the intake was estimated to be 1000, 1500, 2000 and 2000 ml/day for children (3 to <10 years), children (10 to <14 years), adolescents (14 to <18 years) and adults (>18 years), respectively. For the mean chronic drinking pattern, the intake was estimated to be 58, 65, 64 and 71 ml/day for children (3 to <10 years), children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years), respectively. For the high chronic drinking pattern, the intake was estimated to be 163, 180, 210 and 320 ml/day for children (3 to <10 years), children (10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years), respectively. The data on toxicity of inositol was very limited. The human study with the longest exposure at highest doses (3 months treatment at maximum tolerated dose) that was available for risk assessment was a clinical study of 40-74 year old smokers with bronchial dysplasia, from which a NOAEL of 18 g/day of myo -inositol was established (Lam et al. 2006). VKM estimated the margins of exposure (MOE) based on the NOAEL established in this study. The MOE is the ratio of the NOAEL value to the exposure. An acceptable MOE value for a NOAEL-based assessment of inositol based on a human study is ≥10, taking into account a factor 10 for the interindividual variation between humans in toxicokinetics and toxicodynamics. Due to the uncertainty regarding the relevance of the study by Lam et al. (2006) for the general healthy population, an additional safety factor of 3 was used. Therefore, an acceptable MOE value was 30. For all age groups, the MOE values were in the range of 857 to 2570 for mean chronic intake and in the range of 367 to 857 for high chronic intake of energy drinks, respectively, i.e. far above the acceptable MOE value of 30. Since neither the sub-optimal human study by Lam et al. (2006) or the animal studies in rodent models of chronic diseases available were on healthy subjects, as a supplement to the MOE values calculated from the human study, comparisons with endogenous production and amounts in food of inositol were also performed. No studies specifically on children (3 to <10 years and 10 to <14 years) and adolescents (14 to <18 years) were identified. Based on the included literature there was no evidence indicating that age affects tolerance or endogenous production of inositol. Therefore, in this risk characterisation a tolerance and an endogenous production of inositol as for adults, based on body weight, was assumed for these age groups. For the high acute drinking pattern, and for the mean chronic and the high chronic drinking patterns all estimated intakes of inositol from energy drinks containing 10 mg/100 ml were far below the endogenous production (57 mg/kg bw per day), and also below the dietary intake (7-14 mg/kg bw per day). VKM concludes that it is unlikely that the exposure to inositol from the high acute, the mean chronic or the high chronic drinking patterns causes adverse health effects in children (3 to <10 years and 10 to <14 years), adolescents (14 to <18 years) and adults (≥18 years).

Miopatías relacionadas a colágeno VI: cuando sospecharlas, cómo identificarlas: aporte de la resonancia magnética muscular / Collagen VI related myopathies: when to suspect, how to identify: the contribution of muscle magnetic resonance

Resumen: Las miopatías secundarias a mutaciones en el colágeno VI (M-COLVI) son las más frecuentes en el hemisferio norte, afectando población adulta y pediátrica. No existen datos de su prevalencia en Latinoamérica. Se caracterizan por presentar una gran variabilidad clínica, desde fenotipos severos, como la distrofia muscular congénita de Ullrich (DMCU), a intermedios y leves como la Miopatía de Bethlem (MB). Su inicio también es variable y se extiende desde el período de recién nacido hasta la vida adulta. Dada la presencia de hiperlaxitud articular, el diagnóstico diferencial se debe realizar con diversas enfermedades del tejido conectivo. El algoritmo diagnóstico clásico en muchos pacientes ha sido insuficiente para orientar el estudio genético de forma adecuada, y a partir de esto la resonancia magnética muscular ha emergido como una herramienta de gran utilidad para una mejor aproxima ción diagnóstica de ésta y otras patologías musculares. Esta revisión tiene como objetivo examinar las formas de presentación, características clínicas, estudio diagnóstico específico, diagnóstico dife rencial y manejo de una de las patologías musculares herediatarias más frecuentes, con énfasis en el aporte de la resonancia magnética muscular.

Abstract: Myopathies secondary to collagen VI mutations (COLVI-M) are the most frequent in the northern hemisphere, affecting the adult and pediatric population. There are no data on its prevalence in Latin America. They are characterized by a great clinical variability, from severe phenotypes, such as Ullrich congenital muscular dystrophy (UCMD), to intermediate and mild ones such as Bethlem myopathy (BM). Its onset is also variable and extends from the neonatal period to adulthood. Given the presence of joint hypermobility, the differential diagnosis should be made with various connective tissue diseases. The classical diagnostic algorithm in many patients has been insufficient to guide the genetic study in an adequate way, and from this the muscular magnetic resonance imaging has emerged as a very useful tool for a better diagnostic approach of this and other muscular pathologies. This ob jective of this review is to study the forms of presentation, clinical characteristics, specific diagnostic study, differential diagnosis and management of one of the most frequent hereditary muscular patho logies, with emphasis on the contribution of muscle magnetic resonance imaging.

Pre-treatment effect of myo-inositol and l-5, methyltetrahydrofolate in ovulation induction oocyte quality and pregnancy outcome in clomiphene resistance polycystic ovarian disease

Background: This study was designed to assess the treatment effect of myo-inositol and l-5, methyltetrahydrofolate in oocyte quality, pregnancy outcome in clomiphene citrate resistance PCOS cases.Methods: Authors conducted prospective open label, randomized, parallel group study in SIMS Hapur, U.P. Eligible patients full filling inclusion criteria were randomized into two groups having 25 patients in each group using myo-inositol 580mg and l-5, methyltetrahydrofolate 800mcg in treatment group and tab folic acid 400mcg in placebo group for 12 weeks. The follow-up visits are on weeks 4, 8 and 12.Results: 12 weeks later, 21 patients in treatment group restored one spontaneous menstrual cycle and 19 patients maintained the normal ovulatory activity in follow up cycle. Ovulation induction done in 18 patients with clomiphene citrate at the dose of 50mg during treatment out of which 10 conceive, as compared with only 9 women out of the 25 women (36 percent) in the placebo group ovulate (P>0.001) out of which 4 conceived. There was significant decrease in Sr. testosterone, DHEA and AMH level and estradiol level, while statically significant increase in Sr. SHBG and FSH level seen in treatment group(p<0.001).Conclusions: In the study, more number of studied patients get back to normal menstrual cyclicity, insulin-lowering activity and its intracellular role in oocyte maturation. Significant Dec seen in serum estradiol level at the day of HCG administration.

Combined treatment with myo-inositol and luteolin selectively suppresses growth of human lung cancer A549 cells possibly by suppressing activation of PDK1 and Akt / 南方医科大学学报

OBJECTIVE@#To study the effects of myo-inositol and luteolin on human lung cancer A549 cells and explore the possible mechanisms.@*METHODS@#A549 cells were treated with different concentrations of myo-inositol and luteolin, either alone or in combination, and the cell viability was examined using MTT assay. A549 cells and human bronchial epithelial Beas-2B cells were treated for 48 h with 10 mmol/L myo-inositol and 20 μmol/L luteolin, alone or in combination, and the cell proliferation was detected using MTT assay; the colony formation and migration of the cells were examined with colony formation assay and wound healing assay, respectively. The protein expression levels in A549 cells were detected using Western blotting.@*RESULTS@#Both myo-inositol and luteolin could dose-dependently inhibit the viability of A549 cells. Treatments with 10 mmol/L myo-inositol, 20 μmol/L luteolin, and both for 48 h caused significant reduction in the cell viability (92%, 83% and 70% of the control level, respectively) and colony number (79%, 73% and 43%, respectively), and significantly lowered the wound closure rate (24.61%, 13.08% and 8.65%, respectively, as compared with 29.99% in the control group). Similar treatments with myoinositol and luteolin alone or in combination produced no significant inhibitory effect on the growth, colony formation or migration of Beas-2B cells. The expressions of p-PDK1 and p-Akt in myo-inositol-treated A549 cells and the expression of pPDK1 in luteolin-treated cells were significantly decreased ( < 0.05), and the decrements were more obvious in the combined treatment group ( < 0.05).@*CONCLUSIONS@#Luteolin combined with myo-inositol can selectively inhibit the proliferation and migration of A549 cells, and these effects are probably mediated, at least in part, by suppressing the activation of PDK1 and Akt.

Construction of a glucaric acid biosensor for screening myo-inositol oxygenase variants / 生物工程学报

Glucaric acid (GA), a top value-added chemical from biomass, has been widely used for prevention and control of diseases and the production of polymer materials. In GA biosynthesis pathway, the conversion of inositol to glucuronic acid that catalyzed by myo-inositol oxygenase is the limiting step. It is necessary to improve MIOX activity. In the present study, we constructed a high-throughput screening system through combing the concentration of GA with the green fluorescent protein fluorescence intensity. By applying this screening system, three positive variants (K59V/R60A, R171S and D276A) screened from the mutant library. In comparison, the recombinant strain Escherichia coli BL21(DE3)/MU-R171S accumulated more GA, 136.5% of that of the parent strain.