Genomic imbalances in craniofacial microsomia.

The aim of this study was to perform 22q11.2 deletion screening and chromosomal microarray analysis (CMA) in individuals clinically diagnosed with craniofacial microsomia (CFM) and review previously published cases of CFM with genomic imbalances. It included 54 individuals who were evaluated by a clinical geneticist. Copy number variants (CNVs) in the 22q11.2 region were investigated by multiplex ligation-dependent probe amplification (MLPA) for all individuals. The CMA was performed only for individuals with additional major features. MLPA revealed pathogenic CNVs at the 22q11 region in 3/54 (5.6%) individuals. CMA revealed pathogenic CNVs in 4/17 (23.5%) individuals, including the three CNVs at the 22q11 region also detected by MLPA, and CNVs classified as variants of unknown significance (VOUS) in 4/17 (23.5%) individuals. Pathogenic alterations were found at the 2p12, 5p15, 13q13, and 22q11 regions. VOUS were found at 3q29, 5q22.2, 5q22.1, and 9p22 regions. All individuals with pathogenic alterations presented additional major features, including congenital heart disease (CHD). The literature review revealed pathogenic CNVs in 17/193 (8.8%) individuals and most of them also presented additional major features, such as CHD, renal anomalies, or developmental delay. In conclusion, CNVs should be investigated in patients with CFM and additional major features.

NAA is a Marker of Disability in Secondary-Progressive MS: A Proton MR Spectroscopic Imaging Study.

BACKGROUND AND PURPOSE: The secondary progressive phase of multiple sclerosis is characterised by disability progression due to processes that lead to neurodegeneration. Surrogate markers such as those derived from MRI are beneficial in understanding the pathophysiology that drives disease progression and its relationship to clinical disability. We undertook a 1H-MRS imaging study in a large secondary progressive MS (SPMS) cohort, to examine whether metabolic markers of brain injury are associated with measures of disability, both physical and cognitive. MATERIALS AND METHODS: A cross-sectional analysis of individuals with secondary-progressive MS was performed in 119 participants. They underwent 1H-MR spectroscopy to obtain estimated concentrations and ratios to total Cr for total NAA, mIns, Glx, and total Cho in normal-appearing WM and GM. Clinical outcome measures chosen were the following: Paced Auditory Serial Addition Test, Symbol Digit Modalities Test, Nine-Hole Peg Test, Timed 25-foot Walk Test, and the Expanded Disability Status Scale. The relationship between these neurometabolites and clinical disability measures was initially examined using Spearman rank correlations. Significant associations were then further analyzed in multiple regression models adjusting for age, sex, disease duration, T2 lesion load, normalized brain volume, and occurrence of relapses in 2 years preceding study entry. RESULTS: Significant associations, which were then confirmed by multiple linear regression, were found in normal-appearing WM for total NAA (tNAA)/total Cr (tCr) and the Nine-Hole Peg Test (ρ = 0.23; 95% CI, 0.06-0.40); tNAA and tNAA/tCr and the Paced Auditory Serial Addition Test (ρ = 0.21; 95% CI, 0.03-0.38) (ρ = 0.19; 95% CI, 0.01-0.36); mIns/tCr and the Paced Auditory Serial Addition Test, (ρ = -0.23; 95% CI, -0.39 to -0.05); and in GM for tCho and the Paced Auditory Serial Addition Test (ρ = -0.24; 95% CI, -0.40 to -0.06). No other GM or normal-appearing WM relationships were found with any metabolite, with associations found during initial correlation testing losing significance after multiple linear regression analysis. CONCLUSIONS: This study suggests that metabolic markers of neuroaxonal integrity and astrogliosis in normal-appearing WM and membrane turnover in GM may act as markers of disability in secondary-progressive MS.

Donation after circulatory death in lung transplantation-five-year follow-up from ISHLT Registry.

BACKGROUND: This study aimed to examine intermediate-term outcomes of lung transplantation (LTx) recipients from donors after circulatory death (DCD). METHODS: We examined the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry data for patients transplanted between January 2003 and June 2017 at 22 centers in North America, Europe, and Australia participating in the DCD Registry. The distribution of continuous variables was summarized as median and interquartile range (IQR) values. Wilcoxon rank sum test was used to compare distribution of continuous variables and chi-square or Fisher's exact test for categorical variables. Kaplan-Meier survival rates after LTx from January 2003 to June 2016 were compared between DCD-III (Maastricht category III withdrawal of life-sustaining therapy [WLST]) only and donors after brain death (DBD) using the log-rank test. Risk factors for 5-year mortality were investigated using Cox multivariate proportional-hazards model. RESULTS: The study cohort included 11,516 lung transplants, of which 1,090 (9.5%) were DCD lung transplants with complete data. DCD-III comprised 94.1% of the DCD cohort. Among the participating centers, the proportion of DCD-LTx performed each year increased from 0.6% in 2003 to 13.5% in 2016. DCD donor management included extubation in 91%, intravenous heparin in 53% and pre-transplant normothermic ex vivo donor lung perfusion in 15%. The median time interval from WLST to cardiac arrest was 15 minutes (IQR: 11-22 minutes) and to cold flush 32 minutes (IQR: 26-41minutes). Compared with DBD, donor age was higher in DCD-III donors (46 years [IQR: 34-55] vs 40 years [IQR: 24-52]), bilateral LTx was performed more often (88.3% vs 76.6%), and more recipients had chronic obstructive pulmonary disease and emphysema as their transplant indication. Five-year survival rates were comparable (63% vs 61%, p = 0.72). In multivariable analysis, recipient and donor ages, indication diagnosis, procedure type (single vs bilateral and double LTx), and transplant era (2003-2009 vs 2010-2016) were independently associated with survival (p < 0.001), but donor type was not (DCD-III vs DBD; hazard ratio, 1.04 [0.90-1.19], p = 0.61). CONCLUSION: This ISHLT DCD Registry report with 5-year follow-up demonstrated similar favorable long-term survival in DCD-III and DBD lung donor recipients at 22 experienced centers globally. These data indicate that more extensive use of DCD-LTx would increase donor organ availability and may reduce waiting list mortality.

Portable normothermic ex-vivo lung perfusion, ventilation, and functional assessment with the Organ Care System on donor lung use for transplantation from extended-criteria donors (EXPAND): a single-arm, pivotal trial.

BACKGROUND: Donor lung use for transplantation is the lowest among solid organ tranplants because of several complex and multifactorial reasons; one area that could have a substantial role is the limited capabilities of cold ischaemic storage. The aim of the EXPAND trial was to evaluate the efficacy of normothermic portable Organ Care System (OCS) Lung perfusion and ventilation on donor lung use from extended-criteria donors and donors after circulatory death, which are rarely used. METHODS: In this single-arm, pivotal trial done in eight institutions across the USA, Germany, and Belgium, lungs from extended-criteria donors were included if fulfilling one or more of the following criteria: a ratio of partial pressure of arterial oxygen (PaO2) to fractional concentration of oxygen inspired air (FiO2) in the donor lung of 300 mm Hg or less; expected ischaemic time longer than 6 h; donor age 55 years or older; or lungs from donors after circulatory death that were recruited and assessed using OCS Lung. Lungs were transplanted if they showed stability of OCS Lung variables, PaO2:FiO2 was more than 300 mm Hg, and they were accepted by the transplanting surgeon. Patients were adult bilateral lung transplant recipients. The primary efficacy endpoint was a composite of patient survival at day 30 post-transplant and absence of The International Society for Heart & Lung Tranplantation primary-graft dysfunction grade 3 (PGD3) within 72 h post-transplantation, with a prespecified objective performance goal of 65%. The primary analysis population was all transplanted recipients. This trial is registered with ClinicalTrials.gov, number NCT01963780, and is now complete. FINDINGS: Between Jan 23, 2014, and Oct 23, 2016, 93 lung pairs were perfused, ventilated, and assessed on the OCS Lung. 12 lungs did not meet OCS transplantation criteria so 81 lungs were suitable for transplantation. Two lungs were excluded for logistical reasons, hence 79 (87%) of eligible lungs were transplanted. The primary endpoint was achieved in 43 (54%) of 79 patients and did not meet the objective performance goal. 35 (44%) of 79 patients had PGD3 within the initial 72 h. 78 (99%) of 79 patients had survived at 30 days post-transplant. The mean number of lung graft-related serious adverse events (respiratory failure and major pulmonary-related infection) was 0·3 events per patient (SD 0·5). INTERPRETATION: Despite missing the objective primary endpoint, the portable OCS Lung resulted in 87% donor lung use for transplantation with excellent clinical outcomes. Many lungs declined by other transplant centres were successfully transplanted using this new technology, which implies its use has the potential to increase the number of lung transplants performed worldwide. Whether similar outcomes could be obtained if these lungs were preserved on ice is unknown and remains an area for future research. FUNDING: TransMedics Inc.

Greater survival despite increased complication rates following lung transplant for alpha-1-antitrypsin deficiency compared to chronic obstructive pulmonary disease.

BACKGROUND: Alpha-1-antitrypsin (A1AT) deficiency (A1ATD) is characterized by accelerated degradation of lung function. We examined our experience with lung transplantation for chronic obstructive pulmonary disease (COPD) with and without A1ATD to compare survival and rates of postoperative surgical complications. METHODS: Patients with A1ATD and non-A1ATD COPD undergoing lung transplantation from 1988-2015 at our institution were analyzed. Complications were categorized into non-gastroenteritis gastrointestinal (GI), wound, airway, and reoperation for bleeding. Overall and complication-free survival were evaluated using Kaplan-Meier curves and Cox proportional hazards models. RESULTS: Three hundred and eighty-five patients underwent lung transplant for COPD (98 A1ATD). For A1ATD, 56.1% underwent single lung transplantation (80.6% for COPD). Early overall and complication-free survival was worse for A1ATD, but this trend reversed at longer follow up. Unadjusted estimated survival showed advantage for COPD at 90 days and 1 year, which attenuated by 5 years and reversed at 10 years (P<0.001). On adjusted analysis, A1ATD was associated with a trend toward lower complication-free survival at 90 days and 1 year, due partly to increased rates of post-transplant GI pathology, particularly in the era of the lung allocation score (LAS). CONCLUSIONS: A1ATD lung recipients had worse short-term complication-free survival but improved long-term survival compared to COPD patients. A1ATD was associated with greater risk of new GI pathology after transplant. Close monitoring of A1ATD patients with timely evaluation of GI complaints after transplant is warranted.

Secondary pulmonary arterial hypertension: to treat or not to treat?

PURPOSE OF REVIEW: The purpose of this review is to review recent literature related to mechanisms and treatment options for 'secondary' (i.e., WHO Groups 3 and 5) pulmonary arterial hypertension (PAH). RECENT FINDINGS: Published randomized controlled trials, in general, do not support the use of approved therapies for 'primary' (i.e., WHO Group 1) PAH patients in patients with Group 3 PAH because of the small numbers of patients and inconsistent benefit. Therefore, we currently recommend against the use of these medications for Group 3 PAH. Similarly, there is limited evidence supporting the use of Group 1 PAH medications in Group 5 patients. In most patients with Group 5 PAH, treatment should be directed to the underlying disease. SUMMARY: The utility of PAH-specific therapy in WHO Group 3 PAH is unclear because of the small numbers of patients evaluated and inconsistent beneficial effects observed. There is limited evidence supporting the use of PAH medications in Group 5 patients, and they may be harmful in some cases.

Clinical implications of donor age: A single-institution analysis spanning 3 decades.

BACKGROUND: We sought to clarify the effect of donor age as a continuous variable on morbidity and mortality in a single-institution experience. METHODS: From 1986 to 2016, 882 adult lung transplants were performed, including 396 in the lung allocation score era. Kaplan-Meier curves and Cox proportional hazards models were used to evaluate the association of donor age with overall survival and bronchiolitis obliterans syndrome (BOS) score ≥1-free survival. Logistic regression was used to evaluate the association with primary graft dysfunction grade 3. Natural cubic splines were used to explore donor age in a continuous fashion to allow for nonlinear relationships. RESULTS: In the lung allocation score era, unadjusted 5-year survival was not significantly different between 3 a priori-defined donor age groups: age <40, 40 to 54, and age ≥55 years (64%, 61%, and 69%, P = .8). Unadjusted 5-year freedom from BOS ≥1 was not significantly different (34%, 20%, and 33%, respectively, P = .1). After we adjusted for comorbidities, cubic spline analysis demonstrated no effect between donor age as a continuous variable and hazard for mortality at 5 years. Similarly, no interaction was seen between donor age and risk of BOS or primary graft dysfunction 3. Adjusted analysis of all 882 transplants pre- and postinception of the lung allocation score also showed no effect of age on 10-year survival. CONCLUSIONS: Long-term survival of lung transplant recipients was not affected by the age of the donor. These findings support the notion that donor age could be relaxed.

Pulmonary Transplant Salvage Using Ultrasound-Assisted Thrombolysis of Subacute Occlusive Main Pulmonary Artery Embolus.

A 53-year-old woman who underwent bilateral lung transplantation 14 months before presented with 2 to 3 weeks of severe exertional dyspnea. Workup revealed a complete embolic occlusion of her left main pulmonary artery related to a femoral deep venous thrombosis. The occlusion did not respond to systemic anticoagulation, and a trial of catheter-directed thrombolysis was pursued. Flow to the left lower lobe was restored after 2 days of thromobolytic therapy. The patient is alive and well at more than 1 year of follow-up.

17p13.3 Microdeletion: Insights on Genotype-Phenotype Correlation.

Microdeletions in the chromosomal region 17p13.3 are associated with neuronal migration disorders, and PAFAB1H1 is the main gene involved. The largest genomic imbalances, including the YWHAE and CRK genes, cause more severe structural abnormalities of the brain and other associated dysmorphic features. Here, we describe a 3-year-old boy with a microdeletion in 17p13.3 presenting with minor facial dysmorphisms, a cleft palate, neurodevelopmental delay, and behavioral disorder with no structural malformation of the brain. The patient was evaluated by a clinician using a standard protocol. Laboratory investigation included GTG-banding, whole-genome AGH, and array-CGH. Whole-genome AGH and array-CGH analysis identified an estimated 2.1-Mb deletion in the 17p13.3 region showing haploinsufficiency of the YWHAE, CRK, H1C1, and OVCA1 genes and no deletion of PAFAH1B1. The complex gene interaction on brain development and function is illustrated in the genotype-phenotype correlation described here. This report reinforces the importance of the 17p13.3 region in developmental abnormalities and highlights the weak implication of the HIC1 and OVCA1 genes in palatogenesis.

Ageing causes prominent neurovascular dysfunction associated with loss of astrocytic contacts and gliosis.

AIMS: Normal neurovascular coupling, mediated by the fine interplay and communication of cells within the neurovascular unit, is critical for maintaining normal brain activity and cognitive function. This study investigated whether, with advancing age there is disruption of neurovascular coupling and specific cellular components of the neurovascular unit, and whether the effects of increasing amyloid (a key feature of Alzheimer's disease) would exacerbate these changes. METHODS: Wild-type mice, in which amyloid deposition is absent, were compared to transgenic amyloid precursor protein (APP) littermates (TgSwDI) which develop age-dependent increases in amyloid. Baseline cerebral blood flow and responses to whisker stimulation were measured. Components of the neurovascular unit (astrocytes, end-feet, pericytes, microglia) were measured by immunohistochemistry. RESULTS: Neurovascular coupling was progressively impaired with increasing age (starting at 12 months) but was not further altered in TgSwDI mice. Aged mice showed reduced vascular pericyte coverage relative to young but this was not related to neurovascular function. Aged mice displayed significant reductions in astrocytic end-feet expression of aquaporin-4 on blood vessels compared to young mice, and a prominent increase in microglial proliferation which correlated with neurovascular function. CONCLUSIONS: Strategies aimed to restore the loss of astrocytic end feet contact and reduce gliosis may improve neurovascular coupling.

Gender differences in long-term survival post-transplant: A single-institution analysis in the lung allocation score era.

The purpose of this study was to clarify the significance of recipient gender status on lung transplant outcomes in a large single-institution experience spanning three decades, we analyzed data from all lung transplants performed in our institution since 1986. Kaplan-Meier curves and Cox proportional hazard models were used to evaluate the effect of recipient characteristics on survival and BOS score ≥1-free survival. Logistic regression analysis was used to explore the association of gender with short-term graft function. About 876 lung transplants were performed between 1986 and 2016. Kaplan-Meier survival estimates at 5 years post-transplant for females vs males in the LAS era were 71% vs 58%. In the LAS era, females showed greater unadjusted BOS≥1-free survival than males (35% vs 25%, P=.02) over 5 years. Female gender was the only factor in the LAS era significantly associated with improved adjusted 5-year survival [HR 0.56 (95% CI 0.33, 0.95) P=.03]. Conversely, in the pre-LAS era female gender was not associated with improved survival. Female recipients showed significantly improved survival over 5 years compared to males in the LAS era. A prospective analysis of biologic and immunologic differences is warranted.

Cook Island artifact geochemistry demonstrates spatial and temporal extent of pre-European interarchipelago voyaging in East Polynesia.

The Cook Islands are considered the "gateway" for human colonization of East Polynesia, the final chapter of Oceanic settlement and the last major region occupied on Earth. Indeed, East Polynesia witnessed the culmination of the greatest maritime migration in human history. Perennial debates have critiqued whether Oceanic settlement was purposeful or accidental, the timing and pathways of colonization, and the nature and extent of postcolonization voyaging-essential for small founding groups securing a lifeline between parent and daughter communities. Centering on the well-dated Tangatatau rockshelter, Mangaia, Southern Cook Islands, we charted the temporal duration and geographic spread of exotic stone adze materials-essential woodworking tools found throughout Polynesia- imported for more than 300 y beginning in the early AD 1300s. Using a technique requiring only 200 mg of sample for the geochemical analysis of trace elements and isotopes of fine-grained basalt adzes, we assigned all artifacts to an island or archipelago of origin. Adze material was identified from the chiefly complex on the Austral Islands, from the major adze quarry complex on Tutuila (Samoa), and from the Marquesas Islands more than 2,400 km distant. This interaction is the only dated example of down-the-line exchange in central East Polynesia where intermediate groups transferred commodities attesting to the interconnectedness and complexity of social relations fostered during postsettlement voyaging. For the Cook Islands, this exchange may have lasted into the 1600s, at least a century later than other East Polynesian archipelagos, suggesting that interarchipelago interaction contributed to the later development of social hierarchies.

Myth or relict: Does ancient DNA detect the enigmatic Upland seal?

The biological status of the so-called 'Upland seal' has remained contentious ever since historical records described a distinct seal from the uplands of New Zealand's (NZ) remote sub-Antarctic islands. Subsequent genetic surveys of the NZ fur seal (Arctocephalus forsteri) detected two highly-divergent mtDNA clades, hypothesized to represent a post-sealing hybrid swarm between 'mainland' (Australia-NZ; A. forsteri) and sub-Antarctic (putative 'Upland'; A. snaresensis) lineages. We present ancient-DNA analyses of prehistoric mainland NZ and sub-Antarctic fur seals, revealing that both of these genetic lineages were already widely distributed across the region at the time of human arrival. These findings indicate that anthropogenic factors did not contribute to the admixture of these lineages, and cast doubt on the validity of the Upland seal. Human-mediated impacts on Arctocephalus genetic diversity are instead highlighted by a dramatic temporal haplotype frequency-shift due to genetic drift in heavily bottlenecked populations following the cessation of industrial-scale harvesting. These extinction-recolonisation dynamics add to a growing picture of human-mediated change in NZ's coastal and marine ecosystems.

Lung transplantation for pulmonary sarcoidosis. Twenty-five years of experience in the USA.

OBJECTIVE: Lung transplantation is the ultimate treatment for end-stage pulmonary sarcoidosis. Post-transplant survival outcomes remain unclear. METHODS: Survival models were used to assess survival and graft outcomes in patients with sarcoid among 20,896 lung transplants performed in the USA. RESULTS: 695 lung recipients were transplanted for pulmonary sarcoidosis. Sarcoid lung recipients had similar median survival rate (69.7 months (IQR 60.2-79.3)) compared with the non-sarcoid lung recipients (63.1 months (IQR 61.4-64.8), p=0.88). In multivariate Cox regression, sarcoidosis was not independently associated with worse mortality (HR 0.96 (95% CI 0.85 to 1.08), p=0.51). Among the sarcoid lung recipients, double lung transplantation (HR 0.76 (0.58 to 0.99), p=0.04) and lung allocation score era (HR 0.74 (0.56 to 0.97), p=0.03) were associated with improved survival. CONCLUSIONS: Recipients of lung transplants for pulmonary sarcoidosis had similar outcomes compared with non-sarcoid lung recipients.

The role of brain-derived neurotrophic factor in learned fear processing: an awake rat fMRI study.

Brain-derived neurotrophic factor (BDNF) signaling is implicated in the etiology of many psychiatric disorders associated with altered emotional processing. Altered peripheral (plasma) BDNF levels have been proposed as a biomarker for neuropsychiatric disease risk in humans. However, the relationship between peripheral and central BDNF levels and emotional brain activation is unknown. We used heterozygous BDNF knockdown rats (BDNF(+/-)) to examine the effects of genetic variation in the BDNF gene on peripheral and central BDNF levels and emotional brain activation as assessed by awake functional magnetic resonance imaging (fMRI). BDNF(+/-) and control rats were trained to associate a flashing light (conditioned stimulus; CS) with foot-shock, and brain activation in response to the CS was measured 24 h later in awake rats using fMRI. Central and peripheral BDNF levels were decreased in BDNF(+/-) rats compared with control rats. Activation of fear circuitry (amygdala, periaqueductal gray, granular insular) was seen in control animals; however, activation of this circuitry was absent in BDNF(+/-) animals. Behavioral experiments confirmed impaired conditioned fear responses in BDNF(+/-) rats, despite intact innate fear responses. These data confirm a positive correlation [r = 0.86, 95% confidence interval (0.55, 0.96); P = 0.0004] between peripheral and central BDNF levels and indicate a functional relationship between BDNF levels and emotional brain activation as assessed by fMRI. The results demonstrate the use of rodent fMRI as a sensitive tool for measuring brain function in preclinical translational studies using genetically modified rats and support the use of peripheral BDNF as a biomarker of central affective processing.

Genotype-phenotype correlation of 16p13.3 terminal duplication and 22q13.33 deletion: Natural history of a patient and review of the literature.

This article reports a patient with a de novo ∼ 9.32 Mb duplication at 16p13.3 and a ∼ 71 Kb deletion at 22q13.33. The patient was followed from 1 month old to 3 years and 8 months of age and presented typical features of the 16p13.3 duplication syndrome. In addition, the patient presents a portal cavernoma, an alteration rarely reported in this condition. Renal agenesis was detected as additional developmental defect. After genomic array and FISH analysis, the karyotype was 46,XX,ins(22;16)(q13;p13.2p13.3). ish ins(22;16)(RP11-35P16+, RP11-27M24+). arr16p13.2p13.3(85,880-9,413,353)×3 dn arr22q13.33 (51,140,789-51,197,838)×1 dn. The authors provide a comprehensive review of the literature. This approach shed light on the genotype-phenotype correlation.

Diagnostic implications of associated defects in patients with typical orofacial clefts / Implicações diagnósticas de defeitos associados em pacientes com fendas orofaciais típicas

ABSTRACT OBJECTIVES: To describe prevalence of associated defects and clinical-genetic characteristics of patients with typical orofacial clefts seen at a reference genetic service. METHODS: Descriptive study conducted between September of 2009 and July of 2014. Two experienced dysmorphologists personally collected and coded clinical data using a validated, standard multicenter protocol. Syndromic cases were defined by the presence of four or more minor defects, one or more major defects, or recognition of a specific syndrome. Fisher's exact and Kruskal-Wallis tests were used for statistics. RESULTS: Among 141 subjects, associated defects were found in 133 (93%), and 84 (59.5%) were assigned as syndromic. Cleft palate was statistically associated with a greater number of minor defects (p < 0.0012) and syndromic assignment (p < 0.001). Syndromic group was associated with low birth weight (p < 0.04) and less access to surgical treatment (p < 0.002). There was no statistical difference between syndromic and non-syndromic groups regarding gender (p < 0.55), maternal age of 35 years and above (p < 0.50), alcohol (p < 0.50) and tobacco consumption (p < 0.11), consanguinity (p < 0.59), recurrence (p < 0.08), average number of pregnancies (p < 0.32), and offspring (p < 0.35). CONCLUSIONS: There is a lack of information on syndromic clefts. The classification system for phenotype assignment adopted in this study has facilitated recognition of high prevalence of associated defects and syndromic cases. This system may be a useful strategy to gather homogeneous samples, to elect appropriate technologies for etiologic and genotype-phenotype approaches, and to assist with multiprofessional care and genetic counseling.

RESUMO OBJETIVOS: Descrever a prevalência de defeitos associados e as características genético-clínicas de pacientes com fendas orofaciais típicas (FOT) em um serviço de referência em genética. MÉTODOS: Estudo descritivo feito entre setembro/2009 e julho/2014. Os dados foram colhidos e codificados por dois observadores clínicos com experiência em dismorfologia, com protocolo validado em estudo multicêntrico. Presença de quatro ou mais defeitos minor, um ou mais defeitos major e diagnóstico de síndrome reconhecida foram critérios usados para classificar o caso como sindrômico. Usou-se teste exato de Fisher para análise de variáveis categóricas e o de Kruskal-Wallis para igualdade de médias. RESULTADOS: Entre 141 sujeitos, 133 (93%) apresentavam ao menos um defeito minor ou major associado, 84 (59,5%) classificados como sindrômicos. As fendas de palato estiveram associadas com maior número de defeitos minor (p < 0,0012) e com a classificação sindrômica (p < 0,01). O grupo sindrômico apresentou maior taxa de baixo peso (p < 0,04) e menor acesso a tratamento cirúrgico (p < 0,02). Não houve diferenças entre os grupos quanto ao gênero (p < 0,55), idade materna ≥ 35 anos (p < 0,50), ingestão de álcool (p < 0,50) e tabagismo (p < 0,11), consanguinidade (p < 0,59), recorrência familial (p < 0,08) e média de gestações (p < 0,32) e de filhos nascidos vivos (p < 0,35). CONCLUSÕES: Existe escassez de informações sobre fendas sindrômicas. O método de classificação fenotípica usado possibilitou a identificação de alta prevalência de defeitos associados e de casos sindrômicos. Esse método seria uma opção para homogeneizar amostras, determinar tecnologias com vistas à investigação etiológica e estudos de correlação genótipo-fenótipo, além de colaborar para intervenção multiprofissional e aconselhamento genético.

Diagnostic implications of associated defects in patients with typical orofacial clefts.

OBJECTIVES: To describe prevalence of associated defects and clinical-genetic characteristics of patients with typical orofacial clefts seen at a reference genetic service. METHODS: Descriptive study conducted between September of 2009 and July of 2014. Two experienced dysmorphologists personally collected and coded clinical data using a validated, standard multicenter protocol. Syndromic cases were defined by the presence of four or more minor defects, one or more major defects, or recognition of a specific syndrome. Fisher's exact and Kruskal-Wallis tests were used for statistics. RESULTS: Among 141 subjects, associated defects were found in 133 (93%), and 84 (59.5%) were assigned as syndromic. Cleft palate was statistically associated with a greater number of minor defects (p<0.0012) and syndromic assignment (p<0.001). Syndromic group was associated with low birth weight (p<0.04) and less access to surgical treatment (p<0.002). There was no statistical difference between syndromic and non-syndromic groups regarding gender (p<0.55), maternal age of 35 years and above (p<0.50), alcohol (p<0.50) and tobacco consumption (p<0.11), consanguinity (p<0.59), recurrence (p<0.08), average number of pregnancies (p<0.32), and offspring (p<0.35). CONCLUSIONS: There is a lack of information on syndromic clefts. The classification system for phenotype assignment adopted in this study has facilitated recognition of high prevalence of associated defects and syndromic cases. This system may be a useful strategy to gather homogeneous samples, to elect appropriate technologies for etiologic and genotype-phenotype approaches, and to assist with multiprofessional care and genetic counseling.

MSC therapy attenuates obliterative bronchiolitis after murine bone marrow transplant.

RATIONALE: Obliterative bronchiolitis (OB) is a significant cause of morbidity and mortality after lung transplant and hematopoietic cell transplant. Mesenchymal stromal cells (MSCs) have been shown to possess immunomodulatory properties in chronic inflammatory disease. OBJECTIVE: Administration of MSCs was evaluated for the ability to ameliorate OB in mice using our established allogeneic bone marrow transplant (BMT) model. METHODS: Mice were lethally conditioned and received allogeneic bone marrow without (BM) or with spleen cells (BMS), as a source of OB-causing T-cells. Cell therapy was started at 2 weeks post-transplant, or delayed to 4 weeks when mice developed airway injury, defined as increased airway resistance measured by pulmonary function test (PFT). BM-derived MSC or control cells [mouse pulmonary vein endothelial cells (PVECs) or lung fibroblasts (LFs)] were administered. Route of administration [intratracheally (IT) and IV] and frequency (every 1, 2 or 3 weeks) were compared. Mice were evaluated at 3 months post-BMT. MEASUREMENTS AND MAIN RESULTS: No ectopic tissue formation was identified in any mice. When compared to BMS mice receiving control cells or no cells, those receiving MSCs showed improved resistance, compliance and inspiratory capacity. Interim PFT analysis showed no difference in route of administration. Improvements in PFTs were found regardless of dose frequency; but once per week worked best even when administration began late. Mice given MSC also had decreased peribronchiolar inflammation, lower levels of hydroxyproline (collagen) and higher frequencies of macrophages staining for the alternatively activated macrophage (AAM) marker CD206. CONCLUSIONS: These results warrant study of MSCs as a potential management option for OB in lung transplant and BMT recipients.