Seroreactivity to HPV-16 proteins in women with early cervical neoplasia

Summary Although serological reactivity to human papillomavirus type 16 (HPV-16) proteins has been demonstrated in patients with invasive cervical carcinoma, the degree of seroreactivity to these proteins in women with preinvasive disease and its relationship to the HPV type associated with the disease are unclear. We obtained sera from 27 women undergoing cone biopsy for cervical precursor lesions and 22 controls and analyzed seroreactivity by Western blot to fusion proteins containing portions of the HPV-16 E4, L1 and L2 open-reading frames (ORFs). Positives were analyzed by scanning densitometry and intensity values for each case plotted relative to controls. Cervical biopsy specimens from patients were analyzed for HPV-16 nucleic acids by DNA · DNA in situ hybridization. Mean intensity values for seroreactivity to the pATH-E4 protein approached significance (P = 0.058) and a significantly higher proportion of cases vs controls registered values over 4.0 for pATH-E4 (26% vs 4.5%;P = 0.04) and pATH-L2 (48% vs 18%;P = 0.03) proteins. A significantly higher mean intensity value for E4 was observed for cases containing HPV-16 DNA vs HPV-16 negative cases or controls. Thus, seroreactivity to HPV-16-derived proteins may be more common in women with preinvasive cervical disease, and for some protein targets (E4) may indicate a relatively type-specific response.Supported in part by grants from the National Cancer Institute [CA 47676 (C.P.C.)], American Cancer Society [MV-395 (C.P.C.)] and an institutional support grant (J.K.R.). Dr. Crum is a recipient of a Physician Scientist Award from the National Institute of Allergy and Infectious Disease (AI00628)     

IL-33-ST2 pathway regulates AECII transdifferentiation by targeting alveolar macrophage in a bronchopulmonary dysplasia mouse model

Evidence points to the indispensable function of alveolar macrophages (AMs) in normal lung development and tissue homeostasis. However, the importance of AMs in bronchopulmonary dysplasia (BPD) has not been elucidated. Here, we identified a significant role of abnormal AM proliferation and polarization in alveolar dysplasia during BPD, which is closely related to the activation of the IL-33-ST2 pathway. Compared with the control BPD group, AMs depletion partially abolished the epithelialmesenchymal transition process of AECII and alleviated pulmonary differentiation arrest. In addition, IL-33 or ST2 knockdown has protective effects against lung injury after hyperoxia, which is associated with reduced AM polarization and proliferation. The protective effect disappeared following reconstitution of AMs in injured IL-33 knockdown mice, and the differentiation of lung epithelium was blocked again. In conclusion, the IL-33-ST2 pathway regulates AECII transdifferentiation by targeting AMs proliferation and polarization in BPD, which shows a novel strategy for manipulating the IL-33–ST2-AMs axis for the diagnosis and intervention of BPD.     

Higher medially-directed joint reaction forces are a characteristic of dysplastic hips: A comparative study using subject-specific musculoskeletal models

Acetabular dysplasia is a known cause of hip osteoarthritis. In addition to abnormal anatomy, changes in kinematics, joint reaction forces (JRFs), and muscle forces could cause tissue damage to the cartilage and labrum, and may contribute to pain and fatigue. The objective of this study was to compare lower extremity joint angles, moments, hip JRFs and muscle forces during gait between patients with symptomatic acetabular dysplasia and healthy controls. Marker trajectories and ground reaction forces were measured in 10 dysplasia patients and 10 typically developing control subjects. A musculoskeletal model was scaled in OpenSim to each subject and subject-specific hip joint centers were determined using reconstructions from CT images. Joint kinematics and moments were calculated using inverse kinematics and inverse dynamics, respectively. Muscle forces and hip JRFs were estimated with static optimization. Inter-group differences were tested for statistical significance (p ≤ 0.05) and large effect sizes (d ≥ 0.8). Results demonstrated that dysplasia patients had higher medially directed JRFs. Joint angles and moments were mostly similar between the groups, but large inter-group effect sizes suggested some restriction in range of motion by patients at the hip and ankle. Higher medially-directed JRFs and inter-group differences in hip muscle forces likely stem from lateralization of the hip joint center in dysplastic patients. Joint force differences, combined with reductions in range of motion at the hip and ankle may also indicate compensatory strategies by patients with dysplasia to maintain joint stability.     

Monostotic fibrous dysplasia in the temporal bone: A late prehistoric occurrence

Fibrous dysplasia, characterized by benign osteolytic and osteoblastic lesions may involve one or several bones. Recent investigators have suggested that it may be merely a phase of what have previously been thought to be several different bone disease. Isolated fibrous dysplasia in the temporal bone is infrequent. Several reports of this disease have appeared in the literature of paleopathology, but none involved only the temporal bone. Monostotic involvement of the right temporal bone was discovered in the skull of an adult male recovered from an archeological site dating from the Late Mississippian period (A. D. 1,350–A. D. 1,650). It will provide an opportunity for preliminary documentation of the antiquity of this disease in the southeastern portion of the United States.     

Mechanisms of bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is a chronic lung disease affecting premature infants with long term effect on lung function into adulthood. Multiple factors are involved in the development of BPD. This review will summarize the different mechanisms leading to this disease and highlight recent bench and clinical research targeted at understanding the role of the mesenchyme (both its cellular and extracellular components) in the pathogenesis of BPD.     

A Japanese child with geleophysic dysplasia caused by a novel mutation of FBN1

Geleophysic dysplasia (GD) is a rare disorder characterized by severe short stature, short hands and feet, limited joint mobility, skin thickening, characteristic facial features (e.g., a “happy” face), and cardiac valvular disorders that often result in an early death. The genes ADAMTSL2 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif-like 2) and FBN1 (fibrillin 1) were recently identified as causative genes for GD. Here, we describe a 10-year-old Japanese female with GD who was born to non-consanguineous parents. At the age of 11 months, she was referred to our hospital because of very short stature for her age (− 4.4 standard deviations of the age-matched value) and a “happy” face with full cheeks, a shortened nose, hypertelorism, and a long and flat philtrum, characteristic of GD. Her hands and feet were small, her skin was thickened, and her joint mobility was generally limited. She had cardiac valvular disorders and history of recurrent respiratory failure. Mutation analysis revealed no abnormalities in ADAMTSL2. However, analysis of FBN1 revealed a novel heterozygous mutation (c.5161T > T/G) in exon 41, which encodes transforming growth factor-β-binding protein-like domain 5 (TB5). GD is an extremely rare disorder and, to our knowledge, only one case of GD with an FBN1 mutation has been reported in Japan. Similar to the previously reported cases of GD, the mutation in the current patient was located in the TB5 domain, which suggests that abnormalities in this domain of FBN1 are responsible for GD.     

股骨短缩截骨全髋置换术治疗青年Crowe IV 型髋关节发育不良

目的：总结股骨短缩截骨结合全髋关节置换术治疗青年Crowe IV 型髋关节发育不良（DDH）的近期疗效。方法：2009 年1 月 至2015 年1 月期间我院收治的22 例（24 髋）青年Crowe IV 型髋关节发育不良患者,其中男4 例（5 髋）,女18 例（19 髋）,年龄 17~27 岁,平均22 岁。记录患者术前、术后髋关节功能Harris评分、髋关节疼痛VAS评分和下肢长度差异。收集患者临床及影像 学资料。结果：22 例患者均获随访,随访时间6～72 个月,平均38 个月。截骨端均骨性愈合,愈合时间3～ 6 个月,平均3.2 个月。 Harris 评分由术前（43.2 ± 2.7）分改善至（95.3 ± 2.8）分,效果显著（P＜0.01）,髋关节疼痛VAS评分由术前(6. 0 ± 1. 0)分改善至 (1.0 ± 0.5) 分,疼痛明显缓解（P＜0.05）,下肢长度差异由术前（55.5± 15.5）mm减少至（16.5± 5.5）mm,显著改善（P＜0.01）。术后2 例合并坐骨神经麻痹,但6 个月内症状完全缓解,6 例遗留轻度跛行。随访期间均无假体翻修,未发现材料与宿主的生物相容性反 应。结论：股骨短缩截骨全髋置换术治疗青年Crowe IV 型髋关节发育不良的近期疗效满意,术中综合考虑软组织松解程度与短缩 截骨方式及长度可有效的解决患者肢体短缩、避免神经血管损伤及改善患者术后髋关节功能。     

Selective inactivation of LGI1 in neuronal precursor cells leads to cortical dysplasia in mice

Constitutional mutations in Leucine‐rich glioma inactivated 1 (LGI1) predispose to an autosomal dominant epilepsy syndrome in humans and germline inactivation of LGI1 in mice leads to early onset seizures. LGI1 is highly expressed in the regions involved in neuronal stem cell generation and migration and detailed analysis of the brains in these mice reveals a subtle cortical dysplasia characterized by hypercellularity in the outer cortical layers. To investigate the cellular origin for this cortical dysplasia, we created mice that allow cell‐specific, conditional inactivation of LGI1. Exons 3–4, which contain critical motifs for LGI1 function, were targeted for deletion and, using a CMV‐cre mouse strain, global inactivation of LGI1 led to early onset seizures and the same cortical dysplasia seen in the constitutionally null mice. Similarly, inactivation of LGI1 in cells expressing Nestin, expressed primarily in neuronal precursor cells, led to early onset seizures and cortical dysplasia. In contrast, targeting inactivation of LGI1 in cells expressing Gfap, Camk2a, and parvalbumin, did not lead to cortical dysplasia. This strain of mouse, therefore, allows for a more refined investigation of the cell types involved in the cortical dysplasia seen following inactivation of LGI1 and potentially a better understanding of the molecular mechanisms behind LGI1‐induced epilepsy.     

Mouse models of the laminopathies

The A and B type lamins are nuclear intermediate filament proteins that comprise the bulk of the nuclear lamina, a thin proteinaceous structure underlying the inner nuclear membrane. The A type lamins are encoded by the lamin A gene (LMNA). Mutations in this gene have been linked to at least nine diseases, including the progeroid diseases Hutchinson-Gilford progeria and atypical Werner's syndromes, striated muscle diseases including muscular dystrophies and dilated cardiomyopathies, lipodystrophies affecting adipose tissue deposition, diseases affecting skeletal development, and a peripheral neuropathy. To understand how different diseases arise from different mutations in the same gene, mouse lines carrying some of the same mutations found in the human diseases have been established. We, and others have generated mice with different mutations that result in progeria, muscular dystrophy, and dilated cardiomyopathy. To further our understanding of the functions of the lamins, we also created mice lacking lamin B1, as well as mice expressing only one of the A type lamins. These mouse lines are providing insights into the functions of the lamina and how changes to the lamina affect the mechanical integrity of the nucleus as well as signaling pathways that, when disrupted, may contribute to the disease.