Cervical radiculopathy: Efficiency of CT-guided cervical facet joint corticosteroid injection : 47

Purpose: Cervical foraminal injection performed with a direct approach of the foramen may induce serious neurologic complications. Cervical facet joint (CFJ) injections are easier to perform and safe, and may diffuse in the epidural and foraminal spaces. We analyzed the efficiency and tolerance of CT-guided CFJ slow-acting corticosteroid injection in patients with radiculopathy related to disc herniation. Methods and materials: Pilot study included 17 patients presenting typical cervical radiculopathy related to disc herniation without relief of pain after medical treatment (one month duration). CFJ puncture was performed under CT guidance with a lateral approach. CT control of the CFJ opacification was performed after injections of contrast agent (1 ml), followed by slow-acting corticosteroid (25 mg). Main criteria for judgment was pain relief one month later (delta visual analogical scale VAS for 0 to 100 mm). Diffusion of iodinated contrast agent in the foramen was assessed by two radiologists in consensus. Results: Pain relief was significant at one month (delta VAS 22 ± 23 mm, p = 0.001) and 41% (7/17) of patients had pain relief more than 50%. In cases with foraminal diffusion, pain relief more than 50% occured in 5 patients (50%) and only in 2 patients (29%) in cases without foraminal diffusion. No complication occurred. Conclusion: CT-guided CFJ slow-acting corticosteroid injection is safe and provided good results at one month follow-up. It may be considered as an interesting percutaneous treatment in patients suffering from cervical radicular pain related to disc herniation.

Comparison of foetal US and MRI in the characterisation of congenital lung anomalies.

OBJECTIVES: To compare the accuracy of prenatal ultrasonography (US) to magnetic resonance imaging (MRI) in the characterisation of congenital lung anomalies, and to assess their agreement with final diagnosis. To evaluate the influence of additional MRI information on therapeutic management. METHODS: 26 prenatal congenital lung anomalies detected consecutively between 2006 and 2012 were retrospectively evaluated. Lesions were initially observed at prenatal US and further investigated with MRI. Prenatal US and MRI imaging findings, and suggested diagnosis were compared with the final diagnosis, obtained from autopsies (4), pathological evaluation following surgical resection (15) and postnatal imaging studies (7). RESULTS: Postnatal diagnoses included 7 congenital pulmonary airway malformations, 8 complex lesions, 7 overinflations, 1 sequestration, 1 bronchogenic cyst, 1 blastoma and 1 bilateral lymphangioma. Suggested prenatal US and MRI diagnosis was correct in 34.6% and 46.2% of patients, respectively, mainly isolated lung lesions with typical imaging findings. Nonspecific imaging findings at US and MRI studies were observed in 38.4% of cases. In 42% of the operated anomalies, pathological dissection revealed the presence of complex anomalies. MRI changed the US diagnosis, but not the further management in 9.7% of the lesions. CONCLUSIONS: Prenatal US and MRI showed a high accuracy in the diagnosis of isolated congenital lung lesions with typical imaging findings. However, overall characterisation rates were low, because of both a high percentage of complex lesions and of lesions with nonspecific imaging findings. MRI was better than US in characterising complex lesions, but its additional information did not influence therapy decisions.

Maternal age-specific risk of non-chromosomal anomalies.

OBJECTIVES: To determine the excess risk of non-chromosomal congenital anomaly (NCA) among teenage mothers and older mothers. DESIGN AND SETTING: Population-based prevalence study using data from EUROCAT congenital anomaly registers in 23 regions of Europe in 15 countries, covering a total of 1.75 million births from 2000 to 2004. PARTICIPANTS: A total of 38,958 cases of NCA that were live births, fetal deaths with gestational age > or = 20 weeks or terminations of pregnancy following prenatal diagnosis of a congenital anomaly. MAIN OUTCOME MEASURES: Prevalence of NCA according to maternal age, and relative risk (RR) of NCA and 84 standard NCA subgroups compared with mothers aged 25-29. RESULTS: The crude prevalence of all NCA was 26.5 per 1000 births in teenage mothers (<20 years), 23.8 for mothers 20-24 years, 22.5 for mothers 25-29 years, 21.5 for mothers 30-34 years, 21.4 for mothers 35-39 years and 22.6 for mothers 40-44 years. The RR adjusted for country for teenage mothers was 1.11 (95% CI 1.06-1.17); 0.99 (95% CI 0.96-1.02) for mothers 35-39; and 1.01 (95% CI 0.95-1.07) for mothers 40-44. The pattern of maternal age-related risk varied significantly between countries: France, Ireland and Portugal had higher RR for teenage mothers, Germany and Poland had higher RR for older mothers. The maternal age-specific RR varied for different NCAs. Teenage mothers were at a significantly greater risk (P < 0.01) of gastroschisis, maternal infection syndromes, tricuspid atresia, anencephalus, nervous system and digestive system anomalies while older mothers were at a significantly greater risk (P < 0.01) of fetal alcohol syndrome, encephalocele, oesophageal atresia and thanatophoric dwarfism. CONCLUSIONS: Clinical and public health interventions are needed to reduce environmental risk factors for NCA, giving special attention to young mothers among whom some risk factors are more prevalent. Reassurance can be given to older mothers that their age in itself does not confer extra risk for NCA.

Paper 5: Surveillance of multiple congenital anomalies: implementation of a computer algorithm in European registers for classification of cases.

BACKGROUND: Surveillance of multiple congenital anomalies is considered to be more sensitive for the detection of new teratogens than surveillance of all or isolated congenital anomalies. Current literature proposes the manual review of all cases for classification into isolated or multiple congenital anomalies. METHODS: Multiple anomalies were defined as two or more major congenital anomalies, excluding sequences and syndromes. A computer algorithm for classification of major congenital anomaly cases in the EUROCAT database according to International Classification of Diseases (ICD)v10 codes was programmed, further developed, and implemented for 1 year's data (2004) from 25 registries. The group of cases classified with potential multiple congenital anomalies were manually reviewed by three geneticists to reach a final agreement of classification as "multiple congenital anomaly" cases. RESULTS: A total of 17,733 cases with major congenital anomalies were reported giving an overall prevalence of major congenital anomalies at 2.17%. The computer algorithm classified 10.5% of all cases as "potentially multiple congenital anomalies". After manual review of these cases, 7% were agreed to have true multiple congenital anomalies. Furthermore, the algorithm classified 15% of all cases as having chromosomal anomalies, 2% as monogenic syndromes, and 76% as isolated congenital anomalies. The proportion of multiple anomalies varies by congenital anomaly subgroup with up to 35% of cases with bilateral renal agenesis. CONCLUSIONS: The implementation of the EUROCAT computer algorithm is a feasible, efficient, and transparent way to improve classification of congenital anomalies for surveillance and research.

Mice with chronic GSH deficit display phenotypical anomalies that resemble key aspects of schizophrenia

ABSTRACTSchizophrenia is a major psychiatric disorder occurring with a prevalence of 1% in the worldwide population. It develops progressively with psychosis onset in late adolescence or earlyadulthood. The disorder can take many different facets and has a highly diffuse anddistributed neuropathology including deficits in major neurotransmitter systems,myelination, stress regulation, and metabolism. The delayed onset and the heterogeneouspathology suggest that schizophrenia is a developmental disease that arises from interplayof genetic and environmental factors during sensitive periods. Redox dysregulation due to animbalance between pro-oxidants and antioxidant defence mechanisms is among the riskfactors for schizophrenia. Glutathione (GSH) is the major cellular redox regulator andantioxidant. Levels of GSH are decreased in cerebrospinal fluid, prefrontal cortex and postmortemstriatum of schizophrenia patients. Moreover, polymorphisms of the key GSHsynthesizingenzyme, glutamate-cysteine ligase, modifier (GCLM) subunit, are associatedwith the disease, suggesting that GSH deficit is of genetic origin. Here we used miceknockout (KO) for the GCLM gene, which display chronic GSH deficit (~70 to 80% decrease)to investigate the direct link between redox dysregulation and schizophrenia. Accordingly,we evaluated whether GCLM KO compared to normal wildtype mice display behavioralchanges that relate to schizophrenia symptoms and whether their brains showmorphological, functional or metabolic alterations that resemble those in patients.Moreover, we exposed pubertal GCLM mice to repeated mild stress and measured theirhormonal and behavioral stress reactivity. Our data show that chronic GSH deficit isassociated with altered emotion- and stress-related behaviors, deficient prepulse inhibition,pronounced amphetamine-induced hyperlocomotion but normal spatial learning andworking memory. These changes represent important schizophrenia endophenotypes.Moreover, this particular pattern of change indicates impairment of the ventralhippocampus (VH) and related circuitry as opposed to the dorsal hippocampus (DH), which isimplicated in spatial information processing. This is consistent with a selective deficit ofparvalbumin positive interneurons and gamma oscillation in the VH but not DH. Increasedlevels of circulating stress hormones in KO mice following pubertal stress corroborate VHdysfunction as it is involved in negative feedback control of the stress response. VHstructural and functional deficits are frequently found in the schizophrenic brain. Metabolicevaluation of the developing GCLM KO anterior cortex using in vivo magnetic resonancespectroscopy revealed elevated glutamine (Gln), glutamate (Glu), Gln/Glu and N-acetylaspartate(NAA) during the pre-pubertal period. Similar changes are reported in earlyschizophrenia. Overall, we observe phenotypic anomalies in GSH deficient GCLM KO micethat correspond to major schizophrenia endophenotypes. This supports an important rolefor redox dysregulation in schizophrenia and validates the GCLM KO mouse as model for thedisease. Moreover, our results indicate that puberty may be a sensitive period for redoxsensitivechanges highliting the importance of early intervention. Gln, Gln/Glu, Glu and NAAmay qualify as early metabolic biomarkers to identify young at-risk individuals. Since chronictreatment with NAC normalized most metabolic changes in GCLM KO mice, NAC may be oneadjunct treatment of choice for early intervention in patients.RESUMELa schizophrénie est une maladie psychiatrique majeure avec une prévalence de 1% dans lapopulation. Son développement est progressif, les premières psychoses apparaissant àl'adolescence ou au début de l'âge adulte. La maladie a plusieurs présentations et uneneuropathologie étendue, qui inclut des déficits neurochimiques, métaboliques, de lamyélination et de la régulation du stress. L'émergence tardive et l'hétérogénéité de lapathologie suggèrent que la schizophrénie est une maladie développementale, favorisée pardes facteurs génétiques et environnementaux durant des périodes sensibles. La dérégulationrédox, due à un déséquilibre entre facteurs pro-oxidantes et défenses anti-oxidantes,constitue un facteur de risque. Le glutathion (GSH) est le principal régulateur rédox et antioxidantdes cellules, ses taux sont diminués dans le liquide céphalorachidien, le cortexpréfrontal et le striatum de patients. De plus, des variations du gène codant la sous-unitémodulatrice (GCLM) de la glutamate-cystéine ligase, enzyme de synthèse du GSH, sontassociés la maladie, suggérant que le déficit observé chez les patients est d'originegénétique. Nous avons donc utilisé des souris ayant une délétion du gène GCLM (KO), quiont un déficit chronique en GSH (70-80%), afin d'étudier le lien entre une dérégulation rédoxet la schizophrénie. Nous avons évalué si ces souris présentent des altérationscomportementales analogues aux symptômes de la maladie, et des modificationsstructurelles, fonctionnelles et métaboliques au niveau du cerveau, ressemblant à celles despatients. De plus, nous avons soumis les souris à des stresses modérés durant la puberté,puis mesuré les réponses hormonales et comportementales. Les animaux présentent undéficit pré-attentionnel du traitement des informations moto-sensorielles, un déficit pourcertains apprentissages, une réponse accrue à l'amphétamine, mais leurs mémoires spatialeet de travail sont préservées. Ces atteintes comportementales sont analogues à certainsendophénotypes de la schizophrénie. De plus, ces changements comportementaux sontlargement expliqués par une perturbation morphologique et fonctionnelle de l'hippocampeventral (HV). Ainsi, nous avons observé un déficit sélectif des interneurones immunoréactifsà la parvalbumine et une désynchronisation neuronale dans l'HV. L'hippocampe dorsal,impliqué dans l'orientation spatiale, demeure en revanche intact. L'augmentationd'hormones de stress dans le sang des souris KO suite à un stress prépubertal soutien aussil'hypothèse d'une dysfonction de l'HV, connu pour moduler ce type de réponse. Des déficitsstructurels et fonctionnels dans l'hippocampe antérieur (ventral) ont d'ailleurs été rapportéschez des patients schizophrènes. Par de résonance magnétique, nous avons également suivile profil métabolique du le cortex antérieur au cours du développement postnatal des sourisKO. Ces mesures ont révélé des taux élevés de glutamine (Gln), glutamate (Glu), du ratioGln/Glu, et de N-acétyl-aspartate (NAA) durant la période prépubertale. Des altérationssimilaires sont décrites chez les patients durant la phase précoce. Nous avons donc révélédes anomalies phénotypiques chez les souris GCLM KO qui reflètent certainsendophénotypes de la schizophrénie. Nos résultats appuient donc le rôle d'une dérégulationrédox dans l'émergence de la maladie et le potentiel des souris KO comme modèle. De plus,cette étude met en évidence la puberté comme période particulièrement sensible à unedérégulation rédox, renforçant l'importance d'une intervention thérapeutique précoce. Dansce cadre, Gln, Gln/Glu, Glu and NAA seraient des biomarqueurs clés pour identifier de jeunesindividus à risque. De part son efficacité dans notre modèle, NAC pourrait être unesubstance de choix dans le traitement précoce des patients.

Case-control analysis of paternal age and trisomic anomalies.

OBJECTIVES: To determine whether older paternal age increases the risk of fathering a pregnancy with Patau (trisomy 13), Edwards (trisomy 18), Klinefelter (XXY) or XYY syndrome. DESIGN: Case-control: cases with each of these syndromes were matched to four controls with Down syndrome from within the same congenital anomaly register and with maternal age within 6 months. SETTING: Data from 22 EUROCAT congenital anomaly registers in 12 European countries. PARTICIPANTS: Diagnoses with observed or (for terminations) predicted year of birth from 1980 to 2005, comprising live births, fetal deaths with gestational age ≥ 20 weeks and terminations after prenatal diagnosis of the anomaly. Data include 374 cases of Patau syndrome, 929 of Edwards syndrome, 295 of Klinefelter syndrome, 28 of XYY syndrome and 5627 controls with Down syndrome. MAIN OUTCOME MEASURES: Odds ratio (OR) associated with a 10-year increase in paternal age for each anomaly was estimated using conditional logistic regression. Results were adjusted to take account of the estimated association of paternal age with Down syndrome (1.11; 95% CI 1.01 to 1.23). RESULTS: The OR for Patau syndrome was 1.10 (95% CI 0.83 to 1.45); for Edwards syndrome, 1.15 (0.96 to 1.38); for Klinefelter syndrome, 1.35 (1.02 to 1.79); and for XYY syndrome, 1.99 (0.75 to 5.26). CONCLUSIONS: There was a statistically significant increase in the odds of Klinefelter syndrome with increasing paternal age. The larger positive associations of Klinefelter and XYY syndromes with paternal age compared with Patau and Edwards syndromes are consistent with the greater percentage of these sex chromosome anomalies being of paternal origin.

Seasonality of congenital anomalies in Europe.

BACKGROUND: This study describes seasonality of congenital anomalies in Europe to provide a baseline against which to assess the impact of specific time varying exposures such as the H1N1 pandemic influenza, and to provide a comprehensive and recent picture of seasonality and its possible relation to etiologic factors. METHODS: Data on births conceived in 2000 to 2008 were extracted from 20 European Surveillance for Congenital Anomalies population-based congenital anomaly registries in 14 European countries. We performed Poisson regression analysis encompassing sine and cosine terms to investigate seasonality of 65,764 nonchromosomal and 12,682 chromosomal congenital anomalies covering 3.3 million births. Analysis was performed by estimated month of conception. Analyses were performed for 86 congenital anomaly subgroups, including a combined subgroup of congenital anomalies previously associated with influenza. RESULTS: We detected statistically significant seasonality in prevalence of anomalies previously associated with influenza, but the conception peak was in June (2.4% excess). We also detected seasonality in congenital cataract (April conceptions, 27%), hip dislocation and/or dysplasia (April, 12%), congenital hydronephrosis (July, 12%), urinary defects (July, 5%), and situs inversus (December, 36%), but not for nonchromosomal anomalies combined, chromosomal anomalies combined, or other anomalies analyzed. CONCLUSION: We have confirmed previously described seasonality for congenital cataract and hip dislocation and/or dysplasia, and found seasonality for congenital hydronephrosis and situs inversus which have not previously been studied. We did not find evidence of seasonality for several anomalies which had previously been found to be seasonal. Influenza does not appear to be an important factor in the seasonality of congenital anomalies.

Anorectal anomalies associated with or as part of other anomalies.

Anorectal anomalies occurring with other anomalies or as part of syndromes were analyzed to determine how their epidemiological characteristics differed from those of isolated anal anomalies. Almost 15% of cases were chromosomal, monogenic or teratogenic syndromes, whereas the rest were of unknown cause including sequences (9.3%), VACTERL associations (15.4%) and multiple congenital anomalies (MCA) (60.2%). Almost half of babies with MCA had one or two VACTERL anomalies with distribution frequencies that did not differ significantly from those in babies with the full VACTERL association. There were considerable differences in the frequency of the VACTERL association among babies with different types of anorectal anomaly. Babies with anal anomalies occurring with sequences, VACTERL or MCA showed the same sex differences as babies with isolated anal anomalies, namely male predominance in anal atresia without fistula or cloaca, no sex difference in anal atresia with fistula, and female predominance in ectopic anus and congenital anal fistula. These anomalies, however, were associated with significantly lower mean gestational lengths and birth weights, and higher frequencies of fetal death and pregnancy termination than babies with isolated anal anomalies. Twins were more frequent in sequences, VACTERL and MCA than in isolated anomalies, monogenic syndromes or chromosome anomalies. Five cases were conjoined twins, representing 15% of all cases of twin pregnancies with an anal anomaly. Indeterminate sex was more frequent in babies with anal atresias without fistula than in those with fistula. Anal anomalies are defects of blastogenesis attributable to disorders in expression of pattern determining genes. The differential sex involvement in different types of anal anomaly may be manifestations of expression of the HY/SRY genes during blastogenesis or of X-linkage.

Human papillomavirus (HPV) vaccines as an option for preventing cervical malignancies: (how) effective and safe?

We carried out a systematic review of HPV vaccine pre- and post-licensure trials to assess the evidence of their effectiveness and safety. We find that HPV vaccine clinical trials design, and data interpretation of both efficacy and safety outcomes, were largely inadequate. Additionally, we note evidence of selective reporting of results from clinical trials (i.e., exclusion of vaccine efficacy figures related to study subgroups in which efficacy might be lower or even negative from peer-reviewed publications). Given this, the widespread optimism regarding HPV vaccines long-term benefits appears to rest on a number of unproven assumptions (or such which are at odd with factual evidence) and significant misinterpretation of available data. For example, the claim that HPV vaccination will result in approximately 70% reduction of cervical cancers is made despite the fact that the clinical trials data have not demonstrated to date that the vaccines have actually prevented a single case of cervical cancer (let alone cervical cancer death), nor that the current overly optimistic surrogate marker-based extrapolations are justified. Likewise, the notion that HPV vaccines have an impressive safety profile is only supported by highly flawed design of safety trials and is contrary to accumulating evidence from vaccine safety surveillance databases and case reports which continue to link HPV vaccination to serious adverse outcomes (including death and permanent disabilities). We thus conclude that further reduction of cervical cancers might be best achieved by optimizing cervical screening (which carries no such risks) and targeting other factors of the disease rather than by the reliance on vaccines with questionable efficacy and safety profiles.

Atrial arrhythmias in adult patients with right- versus left-sided congenital heart disease anomalies.

Atrial arrhythmias (AAs) are a common complication in adult patients with congenital heart disease. We sought to compare the lifetime prevalence of AAs in patients with right- versus left-sided congenital cardiac lesions and their effect on the prognosis. A congenital heart disease diagnosis was assigned using the International Disease Classification, Ninth Revision, diagnostic codes in the administrative databases of Quebec, from 1983 to 2005. Patients with AAs were those diagnosed with an International Disease Classification, Ninth Revision, code for atrial fibrillation or intra-atrial reentry tachycardia. To ensure that the diagnosis of AA was new, a washout period of 5 years after entry into the database was used, a period during which the patient could not have received an International Disease Classification, Ninth Revision, code for AA. The cumulative lifetime risk of AA was estimated using the Practical Incidence Estimators method. The hazard ratios (HRs) for mortality, morbidity, and cardiac interventions were compared between those with right- and left-sided lesions after adjustment for age, gender, disease severity, and cardiac risk factors. In a population of 71,467 patients, 7,756 adults developed AAs (isolated right-sided, 2,229; isolated left-sided, 1,725). The lifetime risk of developing AAs was significantly greater in patients with right- sided than in patients with left-sided lesions (61.0% vs 55.4%, p <0.001). The HR for mortality and the development of stroke or heart failure was similar in both groups (HR 0.96, 95% confidence interval [CI] 0.86 to 1.09; HR 0.94, 95% CI 0.80 to 1.09; and HR 1.10, 95% CI 0.98 to 1.23, respectively). However, the rates of cardiac catheterization (HR 0.63, 95% CI 0.55 to 0.72), cardiac surgery (HR 0.40, 95% CI 0.36 to 0.45), and arrhythmia surgery (HR 0.77, 95% CI 0.6 to 0.98) were significantly less for patients with right-sided lesions. In conclusion, patients with right-sided lesions had a greater lifetime burden of AAs. However, their morbidity and mortality were no less than those with left-sided lesions, although the rate of intervention was substantially different.

Survey of prenatal screening policies in Europe for structural malformations and chromosome anomalies, and their impact on detection and termination rates for neural tube defects and Down's syndrome.

OBJECTIVE: To 'map' the current (2004) state of prenatal screening in Europe. DESIGN: (i) Survey of country policies and (ii) analysis of data from EUROCAT (European Surveillance of Congenital Anomalies) population-based congenital anomaly registers. SETTING: Europe. POPULATION: Survey of prenatal screening policies in 18 countries and 1.13 million births in 12 countries in 2002-04. METHODS: (i) Questionnaire on national screening policies and termination of pregnancy for fetal anomaly (TOPFA) laws in 2004. (ii) Analysis of data on prenatal detection and termination for Down's syndrome and neural tube defects (NTDs) using the EUROCAT database. MAIN OUTCOME MEASURES: Existence of national prenatal screening policies, legal gestation limit for TOPFA, prenatal detection and termination rates for Down's syndrome and NTD. RESULTS: Ten of the 18 countries had a national country-wide policy for Down's syndrome screening and 14/18 for structural anomaly scanning. Sixty-eight percent of Down's syndrome cases (range 0-95%) were detected prenatally, of which 88% resulted in termination of pregnancy. Eighty-eight percent (range 25-94%) of cases of NTD were prenatally detected, of which 88% resulted in termination. Countries with a first-trimester screening policy had the highest proportion of prenatally diagnosed Down's syndrome cases. Countries with no official national Down's syndrome screening or structural anomaly scan policy had the lowest proportion of prenatally diagnosed Down's syndrome and NTD cases. Six of the 18 countries had a legal gestational age limit for TOPFA, and in two countries, termination of pregnancy was illegal at any gestation. CONCLUSIONS: There are large differences in screening policies between countries in Europe. These, as well as organisational and cultural factors, are associated with wide country variation in prenatal detection rates for Down's syndrome and NTD.