Internal Malformations Research Articles

Teratogenic effect of 1.3 bis (p-Hydroxyphenyl)urea on Wistar rats (Rattus norvegicus L.)

Pain is a physiological disorder that pregnant women often experience, so they take various medications to relieve the pain. Many pain relievers on the market have teratogenic effects on pregnant women. 1.3 bis(p-Hydroxyphenyl)urea is a modification of p-aminophenol and has analgesic and anti-inflammatory properties and fewer hepatotoxic side effects. However, its safety in pregnant women has not been studied. This research continues our previous research to determine the teratogenic effects on white rat fetuses and toxic effects on pregnant white rats after administering 1.3 bis(p-Hydroxyphenyl)urea. The teratogenic effect test was carried out on pregnant rats divided into five groups with doses of 50, 500 and 1000 mg/kg BW, CMC Sodium 0.5%, and Gabapentin 50 mg/kg BW as the control group. Rats marked as pregnant were given test preparations and observed for toxic symptoms, and then fetal weight, body length, internal malformations and bone malformations were observed surgically. The study showed that administration at 50 and 500 mg/kg BW doses did not have a teratogenic effect. However, at a dose of 1000 mg/kg BW, it causes teratogenic effects characterized by fetal bleeding and bone abnormalities.

Copy number variation analysis in 189 Romanian patients with global developmental delay/intellectual disability

BackgroundDevelopmental delay and intellectual disability represent a common pathology in general population, involving about 3% of the pediatric age population, the genetic etiology being often involved. The aim of this study was to determine the clinically relevant copy number variants in patients diagnosed with global developmental delay/intellectual disability in our population, using the chromosomal microarray analysis.MethodsWe analyzed 189 patients diagnosed with global developmental delay/intellectual disability, presented in Clinical Emergency Hospital for Children, Cluj-Napoca. The patients were completely clinically investigated, including dysmorphic and internal malformations evaluation, psychiatric, neuropsychological and metabolic evaluation, standard karyotyping. Genomic analysis was done using chromosomal microarray analysis.ResultsPathogenic findings (including uniparental disomy) and variants of unknown significance were detected in 53 of 189 patients (28.04%). Pathogenic copy number variants and uniparental disomy were observed in 35 of 189 patients (18.51%). Two patients presented uniparental disomy for chromosome 15, one with clinical phenotype of Prader-Willi syndrome and the other with clinical phenotype with Angelman syndrome. Within the category of pathogenic findings, the recurrent copy number variants were seen in 21 of 35 patients (60%).ConclusionsThe increased percentage of pathogenic structural variants observed in patients with global developmental delay/intellectual disability analyzed by chromosomal microarray technique supports its use in patients with a non-specific phenotype such as these neurodevelopmental disorders. The high percentage of recurrent pathogenic variants between these findings is a finding that support their initial evaluation when a genetic testing algorithm could be a useful option.

Damaging novel mutations in PIGN cause developmental epileptic-dyskinetic encephalopathy: a case report

BackgroundMutations in PIGN, resulting in a glycosylphosphatidylinositol (GPI) anchor deficiency, typically leads to multiple congenital anomalies-hypotonia-seizures syndrome. However, the link between PIGN and epilepsy or paroxysmal non-kinesigenic dyskinesia (PNKD) is not well-described. This study reported a patient with PIGN mutation leading to developmental and epileptic encephalopathy and PNKD, to expand upon the genotype–phenotype correlation of PIGN.Case presentationDuring the first 10 days of life, a girl exhibited paroxysmal staring episodes with durations that ranged from several minutes to hours. These episodes occurred 2–5 times daily and always occurred during wakefulness. Ictal electroencephalography revealed no abnormalities, and PNKD was diagnosed. The patient also exhibited severely delayed psychomotor development and generalized seizures at the age of 4 months. Results of brain magnetic resonance imaging and metabolic screenings were normal, but trio-based whole-exome sequencing identified two novel compound heterozygous PIGN mutations (NM_176787; c.163C > T [p.R55 > X] and c.283C > T [p.R95W]). Flow cytometry analysis of the patient’s granulocytes revealed dramatically reduced expression of GPI-anchored proteins. This indicated that the mutations compromised GPI functions. The patient got seizure-free for 1 year, and her dyskinesia episodes reduced significantly (1–2 times/month) after treatment with levetiracetam (600 mg/day) and clonazepam (1.5 mg/day). No progress was observed with respect to psychomotor development; however, no craniofacial dysmorphic features, cleft lip/palate, brachytelephalangy with nail hypoplasia, and internal malformations have been observed until now (6 years of age).ConclusionThis is the first study to document developmental and epileptic encephalopathy with PNKD in a human with PIGN mutations. This report expanded our understanding of the genotype–phenotype correlation of PIGN, and PIGN may be considered a potentially relevant gene when investigating cases of epilepsy or PNKD.

Evaluation of supramolecular complex of fenbendazole effect on embryonic development

The purpose of the research is to study the embryotropic effect of supramolecular complex of fenbendazole (SMСF).Materials and methods. The experiment to assess the embryotropic properties of SMCF was carried out on 40 white female and 20 male rats in accordance with the Guidelines for the experimental (preclinical) study of new pharmacological substances. Pregnant female rats were divided into 3 experimental and one control groups. SMCF was administered intragastrically on the 1–6 days of embryogenesis (group 1); on the 7–14 days (group 2) and on the 15–19 days (group 3) in three times therapeutic dose – 6,0 mg/kg of active substance. The animals of the control group received saline from the first to the 19th days of pregnancy. Rats were euthanized on the 20th day of pregnancy. The uterus with fetuses was removed after laparotomy, the number of corpora lutea, implantation sites, the number of living, dead and resorbed fetuses were recorded, the weight and diameter of the placenta were determined. The embryos were examined, weighed, the craniocaudal sizes were determined, the levels of total embryonic, preimplantation and postimplantation embryo death were calculated. The fetuses were examined for abnormalities of internal organs and changes in the skeletal system according to the methods of J. G. Wilson (1965) and A. B. Dawson (1926), modified in the department of embryology of the IEM of the USSR Academy of Medical Sciences.Results and discussion. As a result, SMCF does not induce toxic effects on the fetus: mortality rates, size and weight of embryos were at the level of the control group in a threefold therapeutic dose 6,0 mg/kg at intragastric administration on the 1–6; 7–14 and 15–19 days of pregnancy. SMCF did not cause external and internal malformations.

Klinefelter Syndrome and Turner Syndrome.

1. Carole Samango-Sprouse, EdD*,†,‡ 2. Sophia Q. Song, BA‡ 3. Angela E. Lin, MD§ 4. Cynthia M. Powell, MD¶ 5. Andrea L. Gropman, MD*,** 1. *George Washington University, Washington, DC 2. †Florida International University, Miami, FL 3. ‡Department of Research, The Focus Foundation, Davidsonville, MD 4. §Massachusetts General Hospital for Children, Boston, MA 5. ¶University of North Carolina at Chapel Hill, Chapel Hill, NC 6. **Children’s National Medical Center, Washington, DC Sex chromosome aneuploidy (SCA) syndromes refer to disorders with an abnormality of sex chromosome number. The most common are Klinefelter syndrome (KS), resulting from the gain of an X chromosome in males, and Turner syndrome (TS), reflecting the loss of an X chromosome or the presence of a structurally different X chromosome in females. Whereas most patients with KS have nonmosaic 47,XXY, only 40% of women with TS have 45,X; the remainder have a variety of mosaicisms. The syndromes also contrast in that males with KS are characteristically tall, whereas females with TS are typically short unless they receive hormonal treatment. Despite efforts to increase awareness, KS and TS are often underdiagnosed, leading to delayed care. Only 25% of men with KS are ever diagnosed, with fewer than 10% detected prenatally, and with a median age of 27 years for those identified later in life. For TS, the median age at diagnosis is 6.6 years. Although not exclusively, optimal neurocognitive outcomes depend on the timing of diagnosis and access to early targeted treatment, so fortunately the recent development of noninvasive prenatal screening is increasing the early identification of these disorders dramatically. Pediatricians should be aware of signs that allow for early detection, and the importance of prompt referral for testing and therapy. KS occurs in 1 in 660 live births, representing the most common SCA. Affected males have androgen deficiency, which affects endocrine, central nervous system, and neurodevelopmental function. Characteristics include increased height, clinodactyly of the fifth finger, pes planus, and hypogonadism manifesting as …

Craniofacial Anomaly Association with the Internal Malformations in the Pediatric Age Group in Al-Fallujah City-Iraq

Objectives To estimate the prevalence of craniofacial anomalies among Iraqi people and its association with other congenital malformations. Methods A hospital-based cohort study. It was conducted in Iraq, Fallujah city from Jan 2019-April 2019. The pediatric age group below 16 years attending the consultation clinic. Results The prevalence rate of craniofacial anomalies was 2%. There were 43 (54%) males and 37 (46%) females. A 55 cases (69%) out of total 80 cases have an association with other internal congenital malformations, and 25 cases (31%) have no association. Those associated internal malformations were categorized according to their types into congenital heart disease 33(60%), Renal diseases 9 (16%), CNS anomalies 8(15%), and GIT anomalies 5(9%). Conclusions Craniofacial anomalies showed a relatively higher prevalence rate in comparison to other studies worldwide. It was found that the majority of craniofacial anomalies might be associated with other congenital systemic malformations. Furthermore, the necessary actions to identify the frequency and risk factors associated with craniofacial anomalies in the Iraqi population are emphasized to put a better strategy to establish future preventive programs and treatment.

Smith-Lemli-Opitz syndrome - Fetal phenotypes with special reference to the syndrome-specific internal malformation pattern.

BackgroundAutosomal‐recessive SLOS is caused by mutations in the DHCR7 gene. It is defined as a highly variable complex of microcephaly with intellectual disability, characteristic facies, hypospadias, and polysyndactyly. Syndrome diagnosis is often missed at prenatal ultrasound and fetal autopsyMethodsWe performed autopsies and DHCR7 gene analyses in eight fetuses suspected of having SLOS and measured cholesterol values in long‐term formalin‐fixed tissues of an additional museum exhibitResultsFive of the nine fetuses presented classical features of SLOS, including four cases with atrial/atrioventricular septal defects and renal anomalies, and one with additional bilateral renal agenesis and a Dandy‐Walker cyst. These cases allowed for diagnosis at autopsy and subsequent SLOS diagnosis in two siblings. Two fetuses were mildly affected and two fetuses showed additional holoprosencephaly. These four cases and the exhibit had escaped diagnosis at autopsy. The case with bilateral renal agenesis presented a novel combination of a null allele and a putative C‐terminus missense mutation in the DHCR7 geneConclusionsIn view of the discrepancy between the prevalence of SLOS among newborns and the carrier frequency of a heterozygous DHCR7 gene mutation, the syndrome‐specific internal malformation pattern may be helpful not to miss SLOS diagnosis in fetuses at prenatal ultrasound and fetal autopsy

A study of gross congenital malformation at birth

Background: A congenital anomaly is a structural anomaly of any type that is present at birth. Congenital anomalies may be induced by genetic or environmental factors. Most congenital anomalies, however, show the familial patterns expected of multi-factorial inheritance. The aims and objective of this study were to study the incidence of visible congenital malformations at birth, to study risk factors, to find associated internal malformations.Methods: It is a retrospective cross-sectional study carried out in a tertiary care hospital affiliated to a medical college. The Inclusion criteria include all new-borns delivered in the hospital with visible congenital malformations examined within 48 hours of birth. Extramural babies were included if they had presented within 48 hours after birth. The Exclusion criteria include still births were excluded from the study.Results: Percentage of congenital malformation was 1.32%. Most common systems involved were musculoskeletal system (46.34%) followed by genitourinary system (21.34%) and gastrointestinal system (14.02%).Conclusions: All Babies with gross congenital malformation should be screened for internal malformation. The incidence of CNS malformation has reduced than observed in previous studies which suggest awareness about antenatal folic acid supplementation. Other than CNS anomalies, other system anomalies were not diagnosed antenatally despite antenatal ultrasound being done in maximum number of mothers, which suggest use of 3D or 4D scan antenatally.

Development of a non-destructive detection system of Deep Pectoral Myopathy in poultry by dielectric spectroscopy

The trend in meat consumption has changed drastically in the last years, mainly due to the relationship of red and processed meats with cancer and cardiovascular diseases, which has caused a substantial growth in poultry meat consumption, 8% in 2016. Therefore, poultry production has suffered an intensification that has led to an increase in the incidence of internal malformations in chickens and turkeys for fattening, especially in the pectoral muscles, as Deep Pectoral Myopathy (DPM). Currently, industry is not able to detect DPM breasts when sold as whole carcasses. In this context, the use of dielectric spectroscopy, complemented by a deep study of the chemical, biochemical and microstructural transformations of the muscle and the effect that these changes have on the electrical dispersions in radiofrequency range, may become feasible for online DPM detection. For this paper, non-damaged and affected by DPM chicken breasts (pectoralis major and pectoralis minor) was analysed. Permittivity in radiofrequency and microwave ranges were measured in the different tissues: pectoralis minor, major and skin in order to characterize them. Moreover, proteins content, ion content and pH were measured. With this data, a sensor for measuring the permittivity of chicken whole carcass with skin was developed; it consists of two pairs of two flat plates sensor connected to an impedance Agilent analyzer 4294A and can measure the permittivity from 40 Hz to 1 MHz. The results demonstrated the feasibility of the permittivity in radiofrequency range as an potential identification technique of chicken breasts affected by DPM.

PECULIARITIES OF THE TOXIC EFFECT OF DIISONONYL PHTHALATE PLASTICIZER PHTHALATE ON EXPERIMENTAL MODELS

Introduction. The purpose of the study was to determine the characteristics of the biological effect of diisononyl phthalate, a new plasticizer for polymer products. Material and methods. Toxic properties of the compound have been studied in various ways of its entering in the organism of laboratory animals, local irritating, cumulative and skin-resorptive actions have been established, the potential ability of the compound to induce remote effects in experimental models in vivo/in vitro has been revealed. Results and discussion. The obtained data show diisononyl phthalate do not pose a risk of the acute poisoning under intragastric, intraperitoneal, epicutaneous and inhalation modes of exposure, being incapable of inducing signs of the irritation of the skin and mucous membranes, is not allergic. With subchronic intragastric administration of diisononyl phthalate in doses from 10,000 to 100 mg/kg, the dose dependence of toxic effect and its ability to cause chronic polytropic poisoning of the action in the form of disturbance of the pattern of peripheral blood, calcium and phosphorus metabolism and changes in the functional state of internal organs are revealed. In the study of the reproductive toxicity against the background of the administration of the drug at a dose of 10,000 mg/kg, an increase in total postimplantation, embryonic and the postnatal mortality rate was established. Intragastric administration of diisononyl phthalate at the mentioned dose to female animals during pregnancy triggered the formation of multiple (combined), external and internal malformations of embryos that were single in response to a reduced dose of up to 100 mg/kg. Changes in the state of the reproductive function of males have not been established. In the study of mutagenic toxicity in the Ames test, the effect of the compound has not been established to lead to an increase in the number of revertant colonies, which indicates the lack of ability of diisononyl phthalate to induce point mutations. Conclusion. The results of the studies showed that further study of the toxic effect of diisononylphthalate in chronic exposure and in vitro tests is necessary.

Challenging Reproductive Genetic Counseling in Families at High Risk for Rare Genetic Syndromes – A Case Report with Possible Denys-Drash Syndrome

Calculating the recurrence risk is an integral part of everyday practice of the genetic counselor, but certain difficulties occur when explaining it to the parents of a child with a rare dysmorphic syndrome. We present a case of a family with first newborn with multiple anomalies and exitus letalis, registered on the second day. At birth, the baby presented with limb malformations. Additionally, a spontaneous pneumothorax, neonatal cerebral ischemia, and intraamniotic infection were diagnosed. A post-mortem examination revealed additional multiple internal malformations such as patent foramen ovale, bicornuate uterus, accessory spleen, bilateral adrenal hyperplasia, unilateral Wilm’s tumor of the left kidney, diffuse glomerular and interstitial fibrosis, and protein cylinders in dilated renal tubules. Standard GTG banding karyotyping showed a normal male karyotype 46,XY,16qh+ that did not correspond to the female phenotype of the patient’s genitalia. Postmortem findings together with sex phenotype/genotype discordance suggested Denys-Drash syndrome as possible diagnosis. Amplification of all exons but exon 9 of WT1 gene was not successful on DNA extracted from formalin-fixed paraffin-embedded tissue (FFPET) sample. Sanger sequencing of exon 9 did not reveal a causative mutation. In current case the severe neonatal presentation and absence of molecular conformation complicated giving a certain prognosis for the recurrence risk. Reproductive genetic counseling in families with rare genetic conditions could be very challenging.

The external phenotype-skeleton link in post-hatch farmed Chinook salmon (Oncorhynchus tshawytscha).

Skeletal deformities in farmed fish are a recurrent problem. External malformations are easily recognized, but there is little information on how external malformations relate to malformations of the axial skeleton: the external phenotype-skeleton link. Here, this link is studied in post-hatch to first-feed life stages of Chinook salmon (Oncorhynchus tshawytscha) raised at 4, 8 and 12°C. Specimens were whole-mount-stained for cartilage and bone, and analysed by histology. In all temperature groups, externally normal specimens can have internal malformations, predominantly fused vertebral centra. Conversely, externally malformed fish usually display internal malformations. Externally curled animals typically have malformed haemal and neural arches. External malformations affecting a single region (tail malformation and bent neck) relate to malformed notochords and early fusion of fused vertebral centra. The frequencies of internal malformations in both externally normal and malformed specimens show a U-shaped response, with lowest frequency in 8°C specimens. The fused vertebral centra that occur in externally normal specimens represent a malformation that can be contained and could be carried through into harvest size animals. This study highlights the relationship between external phenotype and axial skeleton and may help to set the framework for the early identification of skeletal malformations on fish farms.

THE STUDY OF EMBRYOTOXIC AND TERATOGENIC EFFECTS OF DIISONONYL PHTHALATE

Toxicological studies were conducted on impact of diisononyl phthalate (DINP) on the reproductive system of white vrats..In experiments, A. Dinerman,’s scheme was applied which allows recording embryotropic and teratogenic effects taking into account the dynamics of the development of offspring in the postnatal period. The presence of anomalies in the development of embryos internal organs was determined by the sagittal section method according to W. Wilson. It was found out that intragastric administration of the test compound to females during the pregnancy period at doses of 100, 1000 and 10,000 mg/kg initiated external and internal malformations in embryos. The exposure level of 10,000 mg/kg is characterized by increased rate of total post implantation and embryonic mortality, multiple embryonic developmental defects. At the same time, there were no significant changes in the postnatal development of the offspring compared to the control. In the experiment it was established that the dose of 10 mg/kg is the most inactive dose of DINP at which no signs of teratogenic and embryotropic actions were revealed.

Clinical and genetic characteristics in a group of 45 patients with Turner syndrome (monocentric study).

IntroductionRecent years have seen a shift in perspective on Turner syndrome, as it is no longer considered a significant disability due to therapeutic advances. The delay of diagnosis and the underdiagnosis are common in Turner syndrome, especially because of the great phenotypic variability and lack of firm diagnostic criteria.AimOur first aim was to assess the clinical and the cytogenetic characteristics and growth rate in growth hormone (GH)-treated patients as compared to those with spontaneous growth. The second aim was to analyze the Y chromosomal sequences.Materials and methodsWe analyzed 45 patients diagnosed with Turner syndrome in Genetic Pathology Centre of Cluj Emergency Children’s Hospital. We carried out a study of the clinical features, the correlations between the karyotype and the phenotype, and we also made a research of Y chromosome sequences.ResultsThe average age at diagnosis was 8.9±5.4 years. A significant association was observed between the number of external phenotypical abnormalities and internal malformations (r=0.45), particularly the cardiovascular ones (r=0.44). Patients treated with GH showed improvement in growth rate, with final stature significantly better than in untreated patients; benefits following treatment were greater if diagnosis was made before the age of 5 years. Thirteen percent of patients experienced spontaneous and complete puberty, whereas 30% experienced incomplete puberty. Patients with the 45,X genotype had a greater stature deficit and a higher incidence of cardiac malformations, compared with patients with 45,X/46,XX mosaic karyotype. Y chromosome sequences were found in only one patient, who subsequently underwent gonadectomy.ConclusionThe importance of this study resides, to the best of our knowledge, in the fact that the largest group of patients in Romania was analyzed and assessed. To draw firm conclusions on the most valuable clinical indicators for Turner syndrome diagnosis in clinical practice, studies on large groups of patients should be conducted.

In utero exposure to venlafaxine, a serotonin-norepinephrine reuptake inhibitor, increases cardiac anomalies and alters placental and heart serotonin signaling in the rat.

Human studies are inconsistent with respect to an association between treatment with selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRI/SNRIs) and an increase in the incidence of congenital heart defects. Here we tested the hypothesis that in utero exposure to venlafaxine, a highly prescribed SNRI, increases the incidence of fetal heart defects and alters placental and fetal heart serotonin signaling in the rat. Timed-pregnant Sprague Dawley rats were gavaged daily with venlafaxine hydrochloride (0, 3, 10, 30, or 100 mg/kg/day) from gestation day 8 to 20. On gestation day 21, fetuses were examined for external and internal malformations; placentas and fetal hearts were collected for the analysis of gene expression. Venlafaxine had no effect on the number of live fetuses, fetal body weights, or external morphology in the absence of maternal toxicity. However, venlafaxine significantly increased the placental index (fetal body/placental weight ratio) and the incidence of fetal cardiac anomalies. Venlafaxine exposure decreased placental expression of the serotonin transporter (SERT/Slc6a4) at the transcript and protein levels. In contrast, venlafaxine increased SERT expression in the hearts of female, but not male, fetuses. Expression of the serotonin 2B receptor (5-HT2B /Htr2b) and of fibroblast growth factor 8 was induced in fetal hearts. In utero venlafaxine exposure altered the placental index and induced fetal cardiac anomalies in rats. We propose that the increased incidence of cardiac anomalies is mediated through alterations in serotonin signaling in the placenta and fetal heart. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:1044-1055, 2016. © 2016 Wiley Periodicals, Inc.

The incidence of congenital malformations and variations in Göttingen minipigs.

Knowledge of the incidence of spontaneous congenital abnormalities is critical for the accurate interpretation of findings in teratogenicity studies in any species. In this paper, results of the examination of 1739 neonatal Göttingen Minipigs are presented. Over the 2-year period under consideration, the incidence of external and visceral malformations was less than 0.2 and 0.1%, respectively. The most common external malformations were syndactyly, limb hyperflexion, domed head and scoliosis. The most common internal malformations were undescended testes, ventricular septal defect, diaphragmatic hernia and atrial septal defects. Pentadactyly and variation in the aortic arch's bifurcation (absent truncus bicaroticus) were the most common variations. These data will help support the use of the Göttingen Minipig as a non-rodent species in embryofetal development studies where concerns persist about the availability of background data.

Treatment of long-segment fracture in middle-up part of femoral with long proximal femoral nail antirotation

Objective To investigate the effects of long proximal femoral nail antirotation （PFNA-long） in treating long-segment fracture in middle-up part of femoral. Methods From June 2006 to December 2013, we treated 139 cases long-segment fracture in middle-up part of femoral with long proximal femoral nail antirotation （PFNA, 320-380 mm） by minimally invasive per-cutaneous fixation and autogenous iliac bone graft. Data of 139 patients （104 male and female 35;ages 18 to 86 years, with an aver-age age of 48.8 years）. Type IA 58 cases （41.73%, 58/139）, type IB 25 cases （17.99%, 25/139）, type IC 4 cases （2.88%, 4/139）, type II 28 cases （20.14%, 28/139）, type IIIA 12 cases （8.63%, 12/139）, type IIIB in 5 cases （3.60%, 5/139）, type IV 7 cases （5.04%, 7/139）. The duration from injury to surgery was 3 hours to 12 days, with an average of 4.2 days. The postoperative follow-up was at 1, 2, 3, 6, 9, 12 months, and annually at least. The clinical efficacy was evaluated with Harris hip function score. The postoperative pain was evaluated with visual analogue scale （VAS）. Results The operative time of 139 cases was from 35 to 90 minutes, averaged 45 minutes and the blood loss during surgery averaged 78.6 ml （ranged from 30 to 200 ml）. All patients walked by walking aid appliance after 4 to 10 days postoperatively, apart from 16 cases with serious long grinding fracture. All patients had been followed up for 3 to 37 months （mean 19 months）. No complications, such as infection, lower limb vein infarction, cut-out and breakage of the implants, occurred. However, there were 4 patients with nail broken and 6 patients with hip internal rotation who were treated by secondary operation. There were 5 cases with slight hip external rotation and 8 cases with hip internal reverse-lamb shortening malformation. All fractures healed after 2.8-6.8 months （mean 3.9 months）. According to Harris criteria, the clini-cal results were best in 108 cases, better in 22 cases, good in 8 cases, and bad in 1 case. The excellent and good rate was 93.53%（130/139）. The score for VAS was 0-6 （mean 0.8）, 93 cases in which no pain, mild pain in 33 cases, moderate pain in 13 cases, 25 cases occasionally need to take non-steroidal analgesics. Conclusion Closed reduction or limited open reduction with PFNA-long is an effective treatment for long-segment fracture in middle-up part of femoral, with higher strength in fixation, higher rate of fracture union, early functional recovery and lower rate of complications. Key words: Femoral fractures Fracture fixation; intramedullary Internal fixators

Azadirachta indica treatment on the congenital malformations of fetuses from rats

Ethnopharmacological relevanceAzadirachta indica A. Juss, popularly known as neem, presents medicinal and insecticide properties. However, the repercussions of the neem maternal treatment on fetal development should be investigated. Thus, the aim of this study was to evaluated the effects of Azadirachta indica (neem) on the frequency of congenital malformations in fetuses from rats. Materials and methodsPregnant rats were randomly distributed into three experimental groups: NT=non-treated; TOil=treated with neem seed oil (1.2mL/day); TAP=treated with active principle of Azadirachta indica (azadirachtin—1.0mg/mL/day). The neem oil (1.2mL/day) or azadirachtin (1.0mg/mL/day) treatments were orally administered throughout pregnancy. Blood samples were collected on days 0, 7, 14 and 20 of pregnancy. Oral glucose test tolerance (OGTT) was performed at day 17 of pregnancy for estimation of total area under the curve (AUC). At term, the fetuses were collected and external and internal (visceral and skeletal) malformations were analyzed. ResultsThe data showed that the dams treated with neem seed oil and Azadirachtin had no significant change in glucose levels and AUC. It was also verified that neem oil treatment contributed to increase the frequency of malformation/variation, in particular the visceral in their fetuses, while neither significant result was observed in TAP group. ConclusionIn conclusion, neem seed oil treatment administered during pregnancy caused abnormalities in rat fetuses, showing teratogenic effect but the Azadirachtin (active principle) presented no impairment in the fetuses.

An 11-year-old girl with recurrent bacterial meningitis due to liquorrhea caused by bone malformation of the skull base

The patient is a healthy 11-year-old girl with no history of trauma or hearing impairment. She developed pneumococcal meningitis three times, at ages 7, 10, and 11. Intracranial examination revealed, pore expansion and cerebrospinal fluid leakage in the right internal acoustic foramen, which were attributed to a bone malformation of the base of the skull. A procedure was performed to close the cerebrospinal fluid leakage; no relapse has been observed thus far. Previous case reports indicate that repetitive bacterial meningitis is often caused by internal ear malformation, trauma, tumors, or surgical operation. This case suggests the possibility that underlying disorders may not be apparent in cases of repetitive bacterial meningitis and, more proactive investigations are required to prevent further recurrence of meningitis.

Sirenomelia phenotype in bmp7;shh compound mutants: a novel experimental model for studies of caudal body malformations.

Sirenomelia is a severe congenital malformation of the lower body characterized by the fusion of the legs into a single lower limb. This striking external phenotype consistently associates severe visceral abnormalities, most commonly of the kidneys, intestine, and genitalia that generally make the condition lethal. Although the causes of sirenomelia remain unknown, clinical studies have yielded two major hypotheses: i) a primary defect in the generation of caudal mesoderm, ii) a primary vascular defect that leaves the caudal part of the embryo hypoperfused. Interestingly, Sirenomelia has been shown to have a genetic basis in mice, and although it has been considered a sporadic condition in humans, recently some possible familial cases have been reported. Here, we report that the removal of one or both functional alleles of Shh from the Bmp7-null background leads to a sirenomelia phenotype that faithfully replicates the constellation of external and internal malformations, typical of the human condition. These mutants represent an invaluable model in which we have analyzed the pathogenesis of sirenomelia. We show that the signaling defect predominantly impacts the morphogenesis of the hindgut and the development of the caudal end of the dorsal aortas. The deficient formation of ventral midline structures, including the interlimb mesoderm caudal to the umbilicus, leads to the approximation and merging of the hindlimb fields. Our study provides new insights for the understanding of the mechanisms resulting in caudal body malformations, including sirenomelia.