Degenerative cervical myelopathy: Neuroradiological, neurophysiological and clinical correlations in 27 consecutive cases.

•New insight into prognostic factors for recovery of clinical function following posterior decompression for degenerative cervical myelopathy.•An increase of IOM amplitude of at least 50% coupled with preoperative T2-only and diffuse T2 signal changes on MRI is a positive prognostic factors for clinical improvement 6 months after surgery.•Clinical improvement at 6 months follow-up can be expected in patients with T1 hypo intensity if a diffuse border of the lesion on T2 images is present.

Sometimes they come back: New and old spinal muscular atrophy adults in the era of nusinersen.

BACKGROUND AND PURPOSE: Following the commercial availability of nusinersen, there have been a number of new referrals of adults with spinal muscular atrophy (SMA) not regularly followed in tertiary-care centers or enrolled in any disease registry. METHODS: We compared demographics and disease characteristics, including assessment of motor and respiratory function, in regularly followed patients and newcomers subdivided according to the SMA type. RESULTS: The cohort included 166 adult patients (mean age: 37.09 years): one type I, 65 type II, 99 type III, and one type IV. Of these 166, there were 67 newcomers. There was no significant difference between newcomers and regularly followed patients in relation to age and disease duration. The Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module scores were higher in the regularly followed patients compared to newcomers in the whole cohort and in both SMA II and II. A difference was also found on ventilatory status (p = 0.013) and Cobb's angle >50° (p = 0.039) between the two subgroups. No difference was found in scoliosis surgery prevalence (p > 0.05). CONCLUSIONS: Our results showed differences between the two subgroups, even if less marked in the type III patients. In the type II patients, there was a higher proportion of newcomers who were in the severe end of the spectrum. Of the newcomers, only approximately a third initiated treatment, as opposed to the 51% in the regularly followed patients. The identification of patients who were not part of the registries will help to redefine the overall prevalence of SMA and the occurrence of different phenotypes.

Outcome of fetuses with congenital cytomegalovirus infection and normal ultrasound at diagnosis: systematic review and meta-analysis.

OBJECTIVE: To report the outcome of fetuses with congenital cytomegalovirus (CMV) infection and normal ultrasound at the time of diagnosis, and to evaluate the rate of an additional anomaly detected only on magnetic resonance imaging (MRI). METHODS: Medline, EMBASE, CINAHL and Cochrane databases were searched for studies reporting on the outcome of fetuses with congenital CMV infection. Inclusion criteria were fetuses with confirmed CMV infection and normal ultrasound assessment at the time of the initial evaluation. The outcomes observed were an anomaly detected on a follow-up ultrasound scan, an anomaly detected on prenatal MRI but missed on ultrasound, an anomaly detected on postnatal assessment but missed prenatally, perinatal mortality, symptomatic infection at birth, neurodevelopmental outcome and hearing and visual deficits. Neurodevelopmental outcome was assessed only in cases of isolated CMV infection confirmed at birth. Subgroup analysis was performed according to the trimester in which maternal infection occurred. Random-effects meta-analysis of proportions was used to analyze the data. RESULTS: Twenty-six studies were included, comprising 2603 fetuses with congenital CMV infection, of which 1178 (45.3%) had normal ultrasound at the time of diagnosis and were included in the analysis. The overall rate of an associated central nervous system (CNS) anomaly detected on a follow-up ultrasound scan was 4.4% (95% CI, 1.4-8.8%) (32/523; 15 studies), while the rates of those detected exclusively on prenatal MRI or on postnatal imaging were 5.8% (95% CI, 1.9-11.5%) (19/357; 11 studies) and 3.2% (95% CI, 0.3-9.0%) (50/660; 17 studies), respectively. The rate of an associated extra-CNS anomaly detected on a follow-up ultrasound scan was 2.9% (95% CI, 0.8-6.3%) (19/523; 15 studies), while the rates of those detected exclusively on MRI or on postnatal imaging were 0% (95% CI, 0.0-1.7%) (0/357; 11 studies) and 0.9% (95% CI, 0.3-1.8%) (4/660; 17 studies), respectively. Intrauterine death and perinatal death each occurred in 0.7% (95% CI, 0.3-1.4%) (2/824; 23 studies) of cases. In cases without an associated anomaly detected pre- or postnatally, symptomatic infection was found in 1.5% (95% CI, 0.7-2.7%) (6/548; 19 studies) of infants, the overall rate of a neurodevelopmental anomaly was 3.1% (95% CI, 1.6-5.1%) (16/550; 19 studies), and hearing problems affected 6.5% (95% CI, 3.8-10.0%) (36/550; 19 studies) of children. Subanalyses according to the trimester in which maternal infection occurred were affected by the very small number of included cases and lack of comparison of the observed outcomes in the original studies. Compared with fetuses infected in the second or third trimester, those infected in the first trimester had a relatively higher risk of having an additional anomaly detected on follow-up ultrasound or MRI, abnormal neurodevelopmental outcome and hearing problems. CONCLUSIONS: In fetuses with congenital CMV infection in which no anomalies are detected on prenatal ultrasound or MRI, the risk of adverse postnatal outcome is lower than that reported previously in the published literature when not considering the role of antenatal imaging assessment. The results from this review also highlight the potential role of MRI, even in fetuses with no anomalies detected on ultrasound, as an anomaly can be detected exclusively on MRI in about 6% of cases. The findings from this study could enhance prenatal counseling of pregnancies with congenital CMV infection with normal prenatal imaging. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Hygienic and sanitary standards of housing in Europe: a comparative analysis of nine countries.

In recent years, growing interest was devoted to housing conditions from both scientific community and public health, so they are now considered among the main environmental and social health determinants of health of the population. Aim of the study is to analyze and compare the current regulations regarding housing sanitary requirements in different Countries of the EU (Sweden, United Kingdom, Denmark, the Netherlands, France, Germany, Portugal, Spain) with the contents of the Italian Health Ministerial Decree 5th July 1975. From the websites of the official channels of the various countries the regulations have been downloaded. For the comparison, only the aspects of BCs concerning the scale of the building were examined; the comparison concerned all the requirements of the Health Ministerial Decree of 5.07.1975 and some other parameters (e.g. indoor chemical pollution, ionizing radiation, non-ionizing radiation) not provided for in the Ministerial Decree, treated in the other standards regulations, and relevant for the indoor well-being of the occupants. The authors observe a wide variability in the contents and in the formulation of the hygienic-sanitary requirements among the different Building Codes, above all as regards the dimensional data and some fundamental themes (e.g. heating systems, mechanical ventilation) whose treatment is often not it is updated with respect to the technological-scientific innovation consolidated over the past few years. A diverse approach among European Countries is also observed: from a market-oriented logic (e.g. UK), to a prescriptive one (Italy), to a functionality-oriented (the Netherlands). The comparative analysis we carried out made it possible to identify convergences and divergences in the standards analysed for the different European countries. As far as the Italian legislation on the usability of residential premises, finally, considering the health, social, environmental and economic trends, many standards contained in the MD 5th July 1975 should be reviewed and updated.

Neonatal Developmental Venous Anomalies: Clinicoradiologic Characterization and Follow-Up.

BACKGROUND AND PURPOSE: Although developmental venous anomalies have been frequently studied in adults and occasionally in children, data regarding these entities are scarce in neonates. We aimed to characterize clinical and neuroimaging features of neonatal developmental venous anomalies and to evaluate any association between MR imaging abnormalities in their drainage territory and corresponding angioarchitectural features. MATERIALS AND METHODS: We reviewed parenchymal abnormalities and angioarchitectural features of 41 neonates with developmental venous anomalies (20 males; mean corrected age, 39.9 weeks) selected through a radiology report text search from 2135 neonates who underwent brain MR imaging between 2008 and 2019. Fetal and longitudinal MR images were also reviewed. Neurologic outcomes were collected. Statistics were performed using χ2, Fisher exact, Mann-Whitney U, or t tests corrected for multiple comparisons. RESULTS: Developmental venous anomalies were detected in 1.9% of neonatal scans. These were complicated by parenchymal/ventricular abnormalities in 15/41 cases (36.6%), improving at last follow-up in 8/10 (80%), with normal neurologic outcome in 9/14 (64.2%). Multiple collectors (P = .008) and larger collector caliber (P < .001) were significantly more frequent in complicated developmental venous anomalies. At a patient level, multiplicity (P = .002) was significantly associated with the presence of ≥1 complicated developmental venous anomaly. Retrospective fetal detection was possible in 3/11 subjects (27.2%). CONCLUSIONS: One-third of neonatal developmental venous anomalies may be complicated by parenchymal abnormalities, especially with multiple and larger collectors. Neuroimaging and neurologic outcomes were favorable in most cases, suggesting a benign, self-limited nature of these vascular anomalies. A congenital origin could be confirmed in one-quarter of cases with available fetal MR imaging.

Outcome of twin-twin transfusion syndrome according to Quintero stage of disease: systematic review and meta-analysis.

OBJECTIVES: To report the outcome of pregnancies complicated by twin-twin transfusion syndrome (TTTS) according to Quintero stage. METHODS: MEDLINE, EMBASE and CINAHL databases were searched for studies reporting the outcome of pregnancies complicated by TTTS stratified according to Quintero stage (I-V). The primary outcome was fetal survival rate according to Quintero stage. Secondary outcomes were gestational age at birth, preterm birth (PTB) before 34, 32 and 28 weeks' gestation and neonatal morbidity. Outcomes are reported according to the different management options (expectant management, laser therapy or amnioreduction) for pregnancies with Stage-I TTTS. Only cases treated with laser therapy were considered for those with Stages-II-IV TTTS and only cases managed expectantly were considered for those with Stage-V TTTS. Random-effects head-to-head meta-analysis was used to analyze the extracted data. RESULTS: Twenty-six studies (2699 twin pregnancies) were included. Overall, 610 (22.6%) pregnancies were diagnosed with Quintero stage-I TTTS, 692 (25.6%) were Stage II, 1146 (42.5%) were Stage III, 247 (9.2%) were Stage IV and four (0.1%) were Stage V. Survival of at least one twin occurred in 86.9% (95% CI, 84.0-89.7%) (456/552) of pregnancies with Stage-I, in 85% (95% CI, 79.1-90.1%) (514/590) of those with Stage-II, in 81.5% (95% CI, 76.6-86.0%) (875/1040) of those with Stage-III, in 82.8% (95% CI, 73.6-90.4%) (172/205) of those with Stage-IV and in 54.6% (95% CI, 24.8-82.6%) (5/9) of those with Stage-V TTTS. The rate of a pregnancy with no survivor was 11.8% (95% CI, 8.4-15.8%) (69/564) in those with Stage-I, 15.0% (95% CI, 9.9-20.9%) (76/590) in those with Stage-II, 18.6% (95% CI, 14.2-23.4%) (165/1040) in those with Stage-III, 17.2% (95% CI, 9.6-26.4%) (33/205) in those with Stage-IV and in 45.4% (95% CI, 17.4-75.2%) (4/9) in those with Stage-V TTTS. Gestational age at birth was similar in pregnancies with Stages-I-III TTTS, and gradually decreased in those with Stages-IV and -V TTTS. Overall, the incidence of PTB and neonatal morbidity increased as the severity of TTTS increased, but data on these two outcomes were limited by the small sample size of the included studies. When stratifying the analysis of pregnancies with Stage-I TTTS according to the type of intervention, the rate of fetal survival of at least one twin was 84.9% (95% CI, 70.4-95.1%) (94/112) in cases managed expectantly, 86.7% (95% CI, 82.6-90.4%) (249/285) in those undergoing laser therapy and 92.2% (95% CI, 84.2-97.6%) (56/60) in those after amnioreduction, while the rate of double survival was 67.9% (95% CI, 57.0-77.9%) (73/108), 69.7% (95% CI, 61.6-77.1%) (203/285) and 80.8% (95% CI, 62.0-94.2%) (49/60), respectively. CONCLUSIONS: Overall survival in monochorionic diamniotic pregnancies affected by TTTS is higher for earlier Quintero stages (I and II), but fetal survival rates are moderately high even in those with Stage-III or -IV TTTS when treated with laser therapy. Gestational age at birth was similar in pregnancies with Stages-I-III TTTS, and gradually decreased in those with Stages-IV and -V TTTS treated with laser and expectant management, respectively. In pregnancies affected by Stage-I TTTS, amnioreduction was associated with slightly higher survival compared with laser therapy and expectant management, although these findings may be confirmed only by future head-to-head randomized trials. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Resultado del síndrome de transfusión feto-fetal según el estadio de Quintero de la enfermedad: revisión sistemática y metaanálisis OBJETIVOS: Informar sobre el resultado de los embarazos complicados por el síndrome de transfusión feto-fetal (TTTS, por sus siglas en inglés) según el estadio de Quintero. MÉTODOS: Se hicieron búsquedas en las bases de datos de MEDLINE, EMBASE y CINAHL de estudios que hubieran informado sobre el resultado de embarazos complicados por TTTS, estratificados según el estadio de Quintero (I-V). El resultado primario fue la tasa de supervivencia fetal según el estadio de Quintero. Los resultados secundarios fueron la edad gestacional al nacer, el parto pretérmino (PPT) antes de las 34, 32 y 28 semanas de gestación y la morbilidad neonatal. Los resultados se reportan de acuerdo con las diferentes opciones de tratamiento (expectante, terapia de láser o amniorreducción) para los embarazos con TTTS en Estadio I. Sólo se consideraron los casos tratados con terapia de láser para aquellos con TTTS de las Etapas II-IV y sólo se consideraron los casos tratados de manera expectante para aquellos con TTTS de la Etapa V. Para analizar los datos extraídos se utilizó un metaanálisis directo de efectos aleatorios. RESULTADOS: Se incluyeron veintiséis estudios (2699 embarazos de gemelos). En total, 610 (22,6%) embarazos fueron diagnosticados con TTTS de Estadio I de Quintero, 692 (25,6%) de Estadio II, 1146 (42,5%) de Estadio III, 247 (9,2%) de Estadio IV y cuatro (0,1%) de Estadio V. La supervivencia de al menos un gemelo se produjo en el 86,9% (IC 95%, 84,0-89,7%) (456/552) de los embarazos en Estadio I, en el 85% (IC 95%, 79,1-90,1%) (514/590) de aquellos en Estadio II, en el 81,5% (IC 95%, 76,6-86,0%) (875/1040) de aquellos en Estadio-III, en el 82,8% (IC 95%, 73,6-90,4%) (172/205) de aquellos en Estadio-IV y en el 54,6% (IC 95%, 24,8-82,6%) (5/9) de aquellos en Estadio-V de TTTS. La tasa de embarazos sin supervivientes fue del 11,8% (IC 95%, 8,4-15,8%) (69/564) de aquellos en Estadio-I, 15,0% (IC 95%, 9,9-20,9%) (76/590) de aquellos en Estadio-II, 18,6% (IC 95%, 14,2-23,4%) (165/1040) de aquellos en Estadio-III, 17,2% (IC 95%, 9,6-26,4%) (33/205) de aquellos en Estadio-IV y en el 45,4% (IC 95%, 17,4-75,2%) (4/9) de aquellos en Estadio-V de TTTS. La edad gestacional al nacer fue similar en los embarazos con TTTS en los Estadios I-III, y disminuyó gradualmente en aquellos con TTTS en los Estadios IV y V. En general, la incidencia de PPT y la morbilidad neonatal aumentaron a medida que se incrementó la gravedad del TTTS, pero los datos sobre estos dos resultados se vieron limitados por el pequeño tamaño de la muestra de los estudios incluidos. Al estratificar el análisis de los embarazos con TTTS en Estadio I según el tipo de tratamiento, la tasa de supervivencia fetal de al menos un gemelo fue del 84,9% (IC 95%, 70,4-95,1%) (94/112) en los casos tratados de forma expectante, del 86,7% (IC 95%, 82,6-90.4%) (249/285) en los sometidos a terapia láser y del 92,2% (IC 95%, 84,2-97,6%) (56/60) en los sometidos a amniorreducción, mientras que la tasa de supervivencia doble fue del 67,9% (IC 95%, 57,0-77,9%) (73/108), del 69,7% (IC 95%, 61,6-77,1%) (203/285) y del 80,8% (IC 95%, 62,0-94,2%) (49/60), respectivamente. CONCLUSIONES: La supervivencia en general en los embarazos biamnióticos monocoriónicos afectados por TTTS es mayor en los estadios tempranos de Quintero (I y II), pero las tasas de supervivencia fetal son moderadamente altas incluso en aquellos con TTTS en estadios III o IV cuando se tratan con terapia láser. La edad gestacional al nacer fue similar en los embarazos con TTTS en los Estadios I-III, y disminuyó gradualmente en aquellos con TTTS en los Estadios IV y V tratados con láser y tratamiento expectante, respectivamente. En los embarazos afectados por TTTS en Estadio I, la amniorreducción estuvo asociada con una supervivencia ligeramente mayor en comparación con la terapia de láser y el tratamiento expectante, aunque estos hallazgos solo pueden confirmarse mediante futuros estudios aleatorizados directos. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Alemtuzumab significantly improves posterior fossa syndrome presented as a relapse of multiple sclerosis.

BACKGROUND: Posterior fossa syndrome (PFS) is a rare manifestation of ponto-mesencephalic lesions frequently reported in post-surgical pediatric tumors, rarely described as a consequence of vascular, infective or inflammatory lesions. OBJECTIVE: The aim of this article is to report the clinical and neuroradiological characteristics of a patient with an acute PFS presentation as a relapse in relapsing-remitting MS, significantly responsive to Alemtuzumab treatment. CASE REPORT: 24-year-old patient affected by multiple sclerosis developed motor-cognitive and behavioral syndrome related to an extensive ponto-mesencephalic lesion under Fingolimod treatment. CONCLUSION: Our case highlights the significant and rapid effect of Alemtuzumab therapy on both cognitive and motor symptoms occurring during a MS relapse with atypical neuroradiological localization.

Observational study on hospital building heritage and microbiological air quality in the orthopedic operating theater: the IM.PA.C.T. Project.

BACKGROUND: The study investigated 35 orthopedic OTs [17 with mixed flow (M-OTs), 18 with turbulent flow (T-OTs)]. METHODS: The OTs were divided into two categories based on recurring architectural and construction solutions, collected by a survey form: type-A (recently built or renovated rooms), and type-B (other OTs). Assessment of microbial air contamination (colony forming units (cfu)/m3 obtained by active sampling via Surface Air System) was then performed. RESULTS: In 97% of the OTs, a Total Viable Count (TVC) was within the limits recommended by ISPESL 2009; all A-type OTs, and 94% of B-type passed. The TVC of type-A OTs [median 15 cfu/m3, range 3-158] was lower than that of type-B OTs [median 28 cfu/m3, range 6-206], although the difference was not significant. The number of people in type-A [mean 8.6, range 6-11] was lower than in type-B [mean 9.6, range 7-13] OTs, and when adjusted to the volume of the OT (person/m3), showed a significant correlation with TVC (ρ = 0.383, p <0.05). CONCLUSIONS: In conclusion, the structural factors examined do not appear to significantly affect the microbiological air quality at the specific sampling point. However, further investigations are required to identify the factors that have the greatest effect on TVC.

Persisting Embryonal Infundibular Recess in Morning Glory Syndrome: Clinical Report of a Novel Association.

Morning glory syndrome is characterized by a congenital optic disc defect that resembles the eponymous flower. We present the MR imaging findings of 2 pediatric patients with morning glory disc anomaly and persisting embryonal infundibular recess, another rare malformative finding, a previously unreported association. Neuroradiologists should be aware of the possible presence of a persisting embryonal infundibular recess in patients with morning glory syndrome, to aid in the differential diagnosis including other pituitary malformations such as pituitary stalk duplication.

Determining optimal eluter design by modeling physical dose enhancement in brachytherapy.

PURPOSE: In situ drug release concurrent with radiation therapy has been proposed to enhance the therapeutic ratio of permanent prostate brachytherapy. Both brachytherapy sources and brachytherapy spacers have been proposed as potential eluters to release compounds, such as nanoparticles or chemotherapeutic agents. The relative effectiveness of the approaches has not been compared yet. This work models the physical dose enhancement of implantable eluters in conjunction with brachytherapy to determine which delivery mechanism provides greatest opportunity to enhance the therapeutic ratio. MATERIALS AND METHODS: The combined effect of implanted eluters and radioactive sources were modeled in a manner that allowed the comparison of the relative effectiveness of different types of implantable eluters over a range of parameters. Prostate geometry, source, and spacer positions were extracted from treatment plans used for 125 I permanent prostate implants. Compound concentrations were calculated using steady-state solution to the diffusion equation including an elimination term characterized by the diffusion-elimination modulus (ϕb ). Does enhancement was assumed to be dependent on compound concentration up to a saturation concentration (csat ). Equivalent uniform dose (EUD) was used as an objective to determine the optimal configuration of eluters for a range of diffusion-elimination moduli, concentrations, and number of eluters. The compound delivery vehicle that produced the greatest enhanced dose was tallied for points in parameter space mentioned to determine the conditions under whether there are situations where one approach is preferable to the other. RESULTS: The enhanced effect of implanted eluters was calculated for prostate volumes from 14 to 45 cm3 , ϕb from 0.01 to 4 mm-1 , csat from 0.05 to 7.5 times the steady-state compound concentration released from the surface of the eluter. The number of used eluters (ne ) was simulated from 10 to 60 eluters. For the region of (csat , Φ)-space that results in a large fraction of the gland being maximally sensitized, compound eluting spacers or sources produce equal increase in EUD. In the majority of the remaining (csat , Φ)-space, eluting spacers result in a greater EUD than sources even where sources often produce greater maximal physical dose enhancement. Placing eluting implants in planned locations throughout the prostate results in even greater enhancement than using only source or spacer locations. CONCLUSIONS: Eluting brachytherapy spacers offer an opportunity to increase EUD during the routine brachytherapy process. Incorporating additional needle placements permits compound eluting spacer placement independent of source placement and thereby allowing a further increase in the therapeutic ratio. Additional work is needed to understand the in vivo spatial distribution of compound around eluters, and to incorporate time dependence of both compound release and radiation dose.

Expanding the histopathological spectrum of CFL2-related myopathies.

Congenital myopathies (CMs) caused by mutation in cofilin-2 gene (CFL2) show phenotypic heterogeneity ranging from early-onset and rapid progressive forms to milder myopathy. Muscle histology is also heterogeneous showing rods and/or myofibrillar changes. Here, we report on three new cases, from two unrelated families, of severe CM related to novel homozygous or compound heterozygous loss-of-function mutations in CFL2. Peculiar histopathological changes showed nemaline bodies and thin filaments accumulations together to myofibrillar changes, which were evocative of the muscle findings observed in Cfl2-/- knockout mouse model.

Sensorineural Hearing Loss in a Patient Affected by Congenital Cytomegalovirus Infection: Is It Useful to Identify Comorbid Pathologies?

Sensorineural hearing loss (SNHL) is a common defect with a multifactorial etiology. Congenital cytomegalovirus infection (cCMV) is the most common infectious cause, and its early detection allows a prompt pharmacological treatment that can improve hearing prognosis. In a consistent percentage of profound SNHL, genetic causes and/or inner ear malformations are involved; their prompt diagnosis might change therapeutic options. This study reports a case of a 3- year-old female patient with symptomatic cCMV infection who also exhibits developmental delay, dysmorphic facial features, bilateral hearing loss, and cochlear incomplete partition, type 2, in 7q21.3 deletion. This deletion includes the genes DLX5 and DLX6 , which could be the candidate genes for the ear malformation named incomplete partition, type 2.

Continuous monitoring of noise levels in the Gulf of Catania (Ionian Sea). Study of correlation with ship traffic.

Acoustic noise levels were measured in the Gulf of Catania (Ionian Sea) from July 2012 to May 2013 by a low frequency (<1000Hz) hydrophone, installed on board the NEMO-SN1 multidisciplinary observatory. NEMO-SN1 is a cabled node of EMSO-ERIC, which was deployed at a water depth of 2100m, 25km off Catania. The study area is characterized by the proximity of mid-size harbors and shipping lanes. Measured noise levels were correlated with the passage of ships tracked with a dedicated AIS antenna. Noise power was measured in the frequency range between 10Hz and 1000Hz. Experimental data were compared with the results of a fast numerical model based on AIS data to evaluate the contribution of shipping noise in six consecutive 1/3 octave frequency bands, including the 1/3 octave frequency bands centered at 63Hz and 125Hz, indicated by the Marine Strategy Framework Directive (2008/56/EC).

The impact of comorbidity and PSA doubling time on the risk of death in men experiencing PSA failure following radiation therapy with or with androgen deprivation therapy for unfavorable-risk prostate cancer.

BACKGROUND: The optimal management of men with PSA failure following initial prostate cancer (PC) therapy stratified by comorbidity is unknown. We investigated the impact that PSA doubling time (DT) and comorbidity had on the risk of all-cause mortality (ACM), prostate cancer-specific mortality (PCSM) and other-cause mortality (OCM) following PSA failure. METHODS: Between 1995 and 2001, 206 men with unfavorable-risk PC were randomized to receive radiation therapy alone or in combination with 6 months of androgen deprivation therapy (ADT); 108 men experienced PSA failure and formed the study cohort. Cox and Fine-Gray regression analysis was used to determine whether PSA DT was associated with the risk of ACM and PCSM/OCM, respectively, stratified by comorbidity status using a validated metric. RESULTS: After a median follow-up of 13.71 years following PSA failure, 81 of the 108 men (75%) died. Longer PSA DT was associated with a decreased risk of PCSM in men with no/minimal (adjusted hazard ratio (AHR) 0.33, 95% confidence interval (CI) 0.17-0.65, P=0.001) and moderate/severe comorbidity (AHR 0.014, 95% CI 0.002-0.129, P=0.0002). However, because of the different contributions of the risk of OCM to risk of ACM within comorbidity subgroups, increasing PSA DT was only associated with a decreased risk of ACM in men with no/minimal (AHR 0.69, 95% CI 0.50-0.96, P=0.03) but not moderate/severe comorbidity (AHR 0.95, 95% CI 0.51-1.78, P=0.87). CONCLUSIONS: Both the extent of comorbidity and the PSA DT should be taken into consideration when deciding on appropriate management and/or clinical trial eligibility at the time of PSA failure.

Duration of the anti-androgen in men undergoing 6 months of an LHRH agonist and radiation therapy for unfavorable-risk prostate cancer and the risk of death.

BACKGROUND: Whether adding a first-generation anti-androgen (AA) to a luteinizing hormone-releasing hormone agonist in the radiotherapeutic management of unfavorable-risk prostate cancer (PC) reduces the risk of all-cause and PC-specific mortality (ACM and PCSM) among men within differing comorbidity subgroups is unknown. METHODS: Between 1995 and 2001, 206 men with unfavorable-risk PC were enrolled in a randomized trial comparing radiation with or without 6 months of androgen-deprivation therapy (ADT). Partial AA use (median: 4.2 months) occurred in 29 of the 102 men randomized to ADT. Cox, and Fine and Gray's regressions were used to evaluate the impact of full versus partial AA use on PCSM and ACM-risk within comorbidity subgroups. RESULTS: After a median follow-up of 16.62 years, 156 men died. In men with moderate to severe comorbidity increasing death was observed as treatment transitioned from no to partial to full ADT (P=0.02) with an increased ACM-risk with full versus partial AA use (adjusted hazard ratio (AHR), 2.25 (95% confidence interval (CI), 0.94-5.41); P=0.07); whereas only 1 and no PC deaths occurred in men receiving a partial versus full AA course, respectively. Among men with no or minimal comorbidity there was no decrease in ACM (AHR, 0.97 (95% CI, 0.49-1.91); P=0.92) or PCSM-risk (AHR 0.39 (95% CI 0.07-52.18); P=0.28) in comparing full versus partial AA use. CONCLUSION: Increasing AA use by 2 months does not appear to impact survival in men with localized unfavorable-risk PC and no or minimal comorbidity, but may shorten survival in men with moderate to severe comorbidity, raising concern regarding in whom and for how long the AA should be prescribed.

Novel mutations in KARS cause hypertrophic cardiomyopathy and combined mitochondrial respiratory chain defect.

Mutations in KARS, which encodes for both mitochondrial and cytoplasmic lysyl-tRNA synthetase, have been so far associated with three different phenotypes: the recessive form of Charcot-Mary-Tooth polyneuropathy, the autosomal recessive nonsyndromic hearing loss and the last recently described condition related to congenital visual impairment and progressive microcephaly. Here we report the case of a 14-year-old girl with severe cardiomyopathy associated to mild psychomotor delay and mild myopathy; moreover, a diffuse reduction of cytochrome C oxidase (COX, complex IV) and a combined enzymatic defect of complex I (CI) and complex IV (CIV) was evident in muscle biopsy. Using the TruSight One sequencing panel we identified two novel mutations in KARS. Both mutations, never reported previously, occur in a highly conserved region of the catalytic domain and displayed a dramatic effect on KARS stability. Structural analysis confirmed the pathogenic role of the identified variants. Our findings confirm and emphasize that mt-aminoacyl-tRNA synthetases (mt-ARSs) enzymes are related to a broad clinical spectrum due to their multiple and still unknown functions.

Autophagy regulates satellite cell ability to regenerate normal and dystrophic muscles.

Autophagy is emerging as a key regulatory process during skeletal muscle development, regeneration and homeostasis, and deregulated autophagy has been implicated in muscular disorders and age-related muscle decline. We have monitored autophagy in muscles of mdx mice and human Duchenne muscular dystrophy (DMD) patients at different stages of disease. Our data show that autophagy is activated during the early, compensatory regenerative stages of DMD. A progressive reduction was observed during mdx disease progression, in coincidence with the functional exhaustion of satellite cell-mediated regeneration and accumulation of fibrosis. Moreover, pharmacological manipulation of autophagy can influence disease progression in mdx mice. Of note, studies performed in regenerating muscles of wild-type mice revealed an essential role of autophagy in the activation of satellite cells upon muscle injury. These results support the notion that regeneration-associated autophagy contributes to the early compensatory stage of DMD progression, and interventions that extend activation of autophagy might be beneficial in the treatment of DMD. Thus, autophagy could be a 'disease modifier' targeted by interventions aimed to promote regeneration and delay disease progression in DMD.

MYH7-related myopathies: clinical, histopathological and imaging findings in a cohort of Italian patients.

BACKGROUND: Myosin heavy chain 7 (MYH7)-related myopathies are emerging as an important group of muscle diseases of childhood and adulthood, with variable clinical and histopathological expression depending on the type and location of the mutation. Mutations in the head and neck domains are a well-established cause of hypertrophic cardiomyopathy whereas mutation in the distal regions have been associated with a range of skeletal myopathies with or without cardiac involvement, including Laing distal myopathy and Myosin storage myopathy. Recently the spectrum of clinical phenotypes associated with mutations in MYH7 has increased, blurring this scheme and adding further phenotypes to the list. A broader disease spectrum could lead to misdiagnosis of different congenital myopathies, neurogenic atrophy and other neuromuscular conditions. RESULTS: As a result of a multicenter Italian study we collected clinical, histopathological and imaging data from a population of 21 cases from 15 families, carrying reported or novel mutations in MYH7. Patients displayed a variable phenotype including atypical pictures, as dropped head and bent spine, which cannot be classified in previously described groups. Half of the patients showed congenital or early infantile weakness with predominant distal weakness. Conversely, patients with later onset present prevalent proximal weakness. Seven patients were also affected by cardiomyopathy mostly in the form of non-compacted left ventricle. Muscle biopsy was consistent with minicores myopathy in numerous cases. Muscle MRI was meaningful in delineating a shared pattern of selective involvement of tibialis anterior muscles, with relative sparing of quadriceps. CONCLUSION: This work adds to the genotype-phenotype correlation of MYH7-relatedmyopathies confirming the complexity of the disorder.