Cycles of satellite and transposon evolution in Arabidopsis centromeres.

Centromeres are critical for cell division, loading CENH3 or CENPA histone variant nucleosomes, directing kinetochore formation and allowing chromosome segregation1,2. Despite their conserved function, centromere size and structure are diverse across species. To understand this centromere paradox3,4, it is necessary to know how centromeric diversity is generated and whether it reflects ancient trans-species variation or, instead, rapid post-speciation divergence. To address these questions, we assembled 346 centromeres from 66 Arabidopsis thaliana and 2 Arabidopsis lyrata accessions, which exhibited a remarkable degree of intra- and inter-species diversity. A. thaliana centromere repeat arrays are embedded in linkage blocks, despite ongoing internal satellite turnover, consistent with roles for unidirectional gene conversion or unequal crossover between sister chromatids in sequence diversification. Additionally, centrophilic ATHILA transposons have recently invaded the satellite arrays. To counter ATHILA invasion, chromosome-specific bursts of satellite homogenization generate higher-order repeats and purge transposons, in line with cycles of repeat evolution. Centromeric sequence changes are even more extreme in comparison between A. thaliana and A. lyrata. Together, our findings identify rapid cycles of transposon invasion and purging through satellite homogenization, which drive centromere evolution and ultimately contribute to speciation.

Avoiding the Intercostal Arteries in Percutaneous Thoracic Interventions.

The purpose of this study was to define relevant intercostal artery (ICA) anatomy potentially impacting the safety of thoracic percutaneous interventional procedures. An ICA abutting the upper rib and running in the subcostal groove was defined as the lowest risk zone for interventions requiring a supracostal needle puncture. A theoretical high-risk zone was defined by the ICA coursing in the lower half of the intercostal space (ICS), and a theoretical moderate-risk zone was defined by the ICA coursing below the subcostal groove but in the upper half of the ICS. Arterial phase computed tomography data from 250 patients were analyzed, revealing demographic variability, with high-risk zones extending more laterally with advancing age and with more cranial ribs. Overall, within the 97.5th percentile, an ICS puncture >7-cm lateral to the spinous process incurs moderate risk and >10-cm lateral incurs the lowest risk.

Retroperitoneal ganglioneuroma presenting as lower back pain.

Retroperitoneal ganglioneuroma (RGN) is a rare benign tumor that arises from the retroperitoneal sympathetic ganglia composed of mature Schwann cells, ganglion cells and nerve fibers. These tumors can occur anywhere along the paravertebral sympathetic plexus and occasionally from adrenal medulla. Although they grow in excessive size, they may cause compression to adjacent organ or structures thus giving rise to symptoms. Resecting RGN's is a challenging endeavor, as they tend to encase neighboring vessels to their site of origin. The reported case is a 43-year-old male who presented with lumbar pain that increased progressively in intensity over the last 6 months. Preoperative investigations revealed a large tumor with encasement of the origins of the superior mesenteric artery and bilateral renal arteries. The tumor was completely resected and the final pathology confirmed the diagnosis of RGN.

Knee Diameter and Cross-Sectional Area as Biomarkers for Cartilage Knee Degeneration on Magnetic Resonance Images.

Background and Objectives: Osteoarthritis (OA) of the knee is a degenerative disorder characterized by damage to the joint cartilage, pain, swelling, and walking disability. The purpose of this study was to assess whether demographic and radiologic parameters (knee diameters and knee cross-sectional area from magnetic resonance (MR) images) could be used as surrogate biomarkers for the prediction of OA. Materials and Methods: The knee diameters and cross-sectional areas of 481 patients were measured on knee MR images, and the corresponding demographic parameters were extracted from the patients' clinical records. The images were graded based on the modified Outerbridge arthroscopic classification that was used as ground truth. Receiver-operating characteristic (ROC) analysis was performed on the collected data. Results: ROC analysis established that age was the most accurate predictor of severe knee cartilage degeneration (corresponding to Outerbridge grades 3 and 4) with an area under the curve (AUC) of the specificity-sensitivity plot of 0.865 ± 0.02. An age over 41 years was associated with a sensitivity and specificity for severe degeneration of 82.8% (CI: 77.5-87.3%), and 76.4% (CI: 70.4-81.6%), respectively. The second-best degeneration predictor was the normalized knee cross-sectional area, with an AUC of 0.767 ± 0.04), followed by BMI (AUC = 0.739 ± 0.02), and normalized knee maximal diameter (AUC = 0.724 ± 0.05), meaning that knee degeneration increases with increasing knee diameter. Conclusions: Age is the best predictor of knee damage progression in OA and can be used as surrogate marker for knee degeneration. Knee diameters and cross-sectional area also correlate with the extent of cartilage lesions. Though less-accurate predictors of damage progression than age, they have predictive value and are therefore easily available surrogate markers of OA that can be used also by general practitioners and orthopedic surgeons.

Evolutionary models of amino acid substitutions based on the tertiary structure of their neighborhoods.

Intra-protein residual vicinities depend on the involved amino acids. Energetically favorable vicinities (or interactions) have been preserved during evolution, while unfavorable vicinities have been eliminated. We describe, statistically, the interactions between amino acids using resolved protein structures. Based on the frequency of amino acid interactions, we have devised an amino acid substitution model that implements the following idea: amino acids that have similar neighbors in the protein tertiary structure can replace each other, while substitution is more difficult between amino acids that prefer different spatial neighbors. Using known tertiary structures for α-helical membrane (HM) proteins, we build evolutionary substitution matrices. We constructed maximum likelihood phylogenies using our amino acid substitution matrices and compared them to widely-used methods. Our results suggest that amino acid substitutions are associated with the spatial neighborhoods of amino acid residuals, providing, therefore, insights into the amino acid substitution process.

A Deep-Learning Diagnostic Support System for the Detection of COVID-19 Using Chest Radiographs: A Multireader Validation Study.

MATERIALS AND METHODS: Five publicly available databases comprising normal CXR, confirmed COVID-19 pneumonia cases, and other pneumonias were used. After the harmonization of the data, the training set included 7966 normal cases, 5451 with other pneumonia, and 258 CXRs with COVID-19 pneumonia, whereas in the testing data set, each category was represented by 100 cases. Eleven blinded radiologists with various levels of expertise independently read the testing data set. The data were analyzed separately with the newly proposed artificial intelligence-based system and by consultant radiologists and residents, with respect to positive predictive value (PPV), sensitivity, and F-score (harmonic mean for PPV and sensitivity). The χ2 test was used to compare the sensitivity, specificity, accuracy, PPV, and F-scores of the readers and the system. RESULTS: The proposed system achieved higher overall diagnostic accuracy (94.3%) than the radiologists (61.4% ± 5.3%). The radiologists reached average sensitivities for normal CXR, other type of pneumonia, and COVID-19 pneumonia of 85.0% ± 12.8%, 60.1% ± 12.2%, and 53.2% ± 11.2%, respectively, which were significantly lower than the results achieved by the algorithm (98.0%, 88.0%, and 97.0%; P < 0.00032). The mean PPVs for all 11 radiologists for the 3 categories were 82.4%, 59.0%, and 59.0% for the healthy, other pneumonia, and COVID-19 pneumonia, respectively, resulting in an F-score of 65.5% ± 12.4%, which was significantly lower than the F-score of the algorithm (94.3% ± 2.0%, P < 0.00001). When other pneumonia and COVID-19 pneumonia cases were pooled, the proposed system reached an accuracy of 95.7% for any pathology and the radiologists, 88.8%. The overall accuracy of consultants did not vary significantly compared with residents (65.0% ± 5.8% vs 67.4% ± 4.2%); however, consultants detected significantly more COVID-19 pneumonia cases (P = 0.008) and less healthy cases (P < 0.00001). CONCLUSIONS: The system showed robust accuracy for COVID-19 pneumonia detection on CXR and surpassed radiologists at various training levels.

Gene capture by transposable elements leads to epigenetic conflict in maize.

Transposable elements (TEs) regularly capture fragments of genes. When the host silences these TEs, siRNAs homologous to the captured regions may also target the genes. This epigenetic crosstalk establishes an intragenomic conflict: silencing the TEs has the cost of silencing the genes. If genes are important, however, natural selection may maintain function by moderating the silencing response, which may also advantage the TEs. In this study, we examined this model by focusing on Helitrons, Pack-MULEs, and Sirevirus LTR retrotransposons in the maize genome. We documented 1263 TEs containing exon fragments from 1629 donor genes. Consistent with epigenetic conflict, donor genes mapped more siRNAs and were more methylated than genes with no evidence of capture. However, these patterns differed between syntelog versus translocated donor genes. Syntelogs appeared to maintain function, as measured by gene expression, consistent with moderation of silencing for functionally important genes. Epigenetic marks did not spread beyond their captured regions and 24nt crosstalk siRNAs were linked with CHH methylation. Translocated genes, in contrast, bore the signature of silencing. They were highly methylated and less expressed, but also overrepresented among donor genes and located away from chromosomal arms, which suggests a link between capture and gene movement. Splitting genes into potential functional categories based on evolutionary constraint supported the synteny-based findings. TE families captured genes in different ways, but the evidence for their advantage was generally less obvious; nevertheless, TEs with captured fragments were older, mapped fewer siRNAs, and were slightly less methylated than TEs without captured fragments. Collectively, our results argue that TE capture triggers an intragenomic conflict that may not affect the function of important genes but may lead to the pseudogenization of less-constrained genes.

Serous Microcystic Cystadenocarcinoma of the Pancreas with Synchronous Liver Metastases: Clinical Characteristics and Management.

Serous cystadenocarcinoma of the pancreas is a rare but well-established entity. The origin and evolution of this disorder remain unclear, but even metastatic cases have an excellent prognosis. These tumors are very similar to benign serous cystic neoplasms (SCNs) of the pancreas, except that they tend to be larger, are locally invasive, and present distant metastasis. The most frequent local invasion is adjacent vessels, spleen, stomach, and duodenum. The most common site of distant metastasis is the liver. Diagnosis via imaging as well as pathology examination may be misguided due to atypical characteristics of the tumor. In fact, in some, the diagnosis of malignancy was established only after metastases were detected. We present a 60-year-old female patient with malignant serous microcystic cystadenocarcinoma of the pancreas and liver metastasis that was initially misdiagnosed as a metastatic renal cell carcinoma. The patient underwent tumor resection and liver metastasectomy and she is currently doing well after three years of follow-up, with no tumor recurrence or new metastatic liver nodules based on imaging findings.

Immune-related intestinal pseudo-obstruction associated with nivolumab treatment in a lung cancer patient.

Immune checkpoint inhibition therapy using targeted monoclonal antibodies is a new therapeutic approach with significant survival benefit for patients with several cancer types. However, their use can be associated with unique immune-related adverse effects as a consequence of impaired self-tolerance due to loss of T-cell inhibition via a nonselective activation of the immune system. Nivolumab is an anti-PD-1 immune checkpoint inhibitor that was recently developed for cancer immunotherapy with remarkable responses in nonsmall cell lung cancer patients. We present a 62-year-old Caucasian male with recurrent lung adenocarcinoma and currently under third-line therapy with nivolumab, who was admitted in our hospital with abdominal distension. Radiologic findings were consistent with small bowel ileus. After four days of conservative treatment, the patient underwent exploratory laparotomy where no cause of ileus was discovered. Postoperative the ileus persisted and considering that an adverse effect of the immune checkpoint inhibition therapy occurred, the patient received high-dose prednisone resulting in gradual improvement of symptoms. Immune checkpoint inhibitors may induce adverse effects to unaffected organ systems and tissues including the skin, gastrointestinal, hepatic, pulmonary, and endocrine system. The mainstay treatment consists of immunosuppression with corticosteroids in the majority of cases. As the clinical use of immune checkpoint inhibitors is expanding rapidly, there is an emergence of unique immune-related adverse effects in a growing patient population. Gaining early awareness is essential in these patients in order to ensure prompt diagnosis and management.

Giant Juvenile Fibroadenoma in a 12-Year-Old Girl: Ultrasonography, Elastography, Clinical, and Pathology Findings of This Rare Type of Fibroadenoma.

A 12-year-old girl was referred to our radiology department with a rapidly enlarging mass in the right breast. Fine-needle aspiration cytology was suggestive of fibroadenoma. Total excision of the mass was done, and diagnosis was confirmed by histopathology.

Biliary Mucinous Cystic Neoplasm of the Liver with Ovarian Stroma and Elevated Serum and Cystic Fluid Cancer Antigen 19-9 Levels.

Biliary mucinous cystic neoplasms of the liver are rare cystic tumors comprising less than 5% of the liver cystic neoplasms. These tumors demonstrate a female predominance and entail a risk of malignant transformation. We present a 56-year-old female patient with a multiloculated liver cystic lesion measuring 22 cm who underwent a cystectomy with en bloc resection of the liver segments II, III, and cholecystectomy. Serum cancer antigen 19.9 was 4,122.00 U/ml, supporting the diagnosis of a biliary cystic tumor. The cytology of the cystic fluid was negative for malignancy and intracystic fluid cancer antigen 19.9 level was measured over 12,000.00 U/l. The patient is free of recurrence at one-year follow up. Although a rare entity, the biliary mucinous cystic neoplasms should be considered in the differential diagnosis in the patients with liver cystic tumors. The appropriate management with complete surgical resection with negative margins is recommended given the risk of recurrence and malignant transformation.

Granuloma Mimicking Local Recurrence on PET/CT after Liver Resection of Colorectal Liver Metastasis: A Case Report.

Positron emission tomography-computed tomography (PET/CT) improves the diagnostic interpretation of fluorine-18 fluorodeoxyglucose (18F-FDG ) PET and CT in oncologic patients and has an impact on both diagnostic and therapeutic aspects of patient management. However, false positive findings from the PET/CT imaging should be taken into consideration as they mislead physicians into improper therapeutic actions. We present a 48-year-old female patient with a history of left colectomy for colorectal cancer and subsequent liver metastasectomy. After one year of follow-up, she presented with a highly suspicious lesion in the liver, which was confirmed on PET/CT as a metastatic liver tumor. Consequently, the patient underwent surgical excision of the tumor, and the definitive histological diagnosis showed a granulomatous tissue with giant cells and foreign body tissue reaction. Based on this report, we briefly review the dangerous pitfalls from radiological and PET/CT imaging concerning the preoperative diagnostic workup examination, as they may significantly alter the treatment plan in oncologic patients.

Diagnostic and Therapeutic Challenges of Intrahepatic Biliary Cystadenoma and Cystadenocarcinoma: A Report of 10 Cases and Review of the Literature.

The objective of this study was to present our experience with intrahepatic biliary cystadenomas and cystadenocarcinomas in 10 patients surgically managed in our department. Intrahepatic biliary cystadenomas and cystadenocarcinomas are rare cystic tumors that are often misdiagnosed preoperatively as simple cysts or hydatid cysts. They recur after incomplete resection and entail a risk of malignant transformation to cystadenocarcinoma. A retrospective review was conducted of patients with histologically confirmed intrahepatic biliary cystadenomas and cystadenocarcinomas between August 2004 and February 2013 who were surgically managed in our department. A total of 10 patients, 9 female and 1 male (mean age, 50 years), with cystic liver were reviewed. The size of the cysts ranged between 3.5 and 16 cm (mean, 10.6). Five patients had undergone previous interventions elsewhere and presented with recurrences. Liver resections included 6 hepatectomies, 2 bisegmentectomies, 1 extended right hepatectomy, and 1 enucleation due to the central position and the large size of the lesion. Pathology reports confirmed R0 resections in all cases. All patients were alive after a median follow-up of 6 years (range, 1-10 years), and no recurrence was detected. Intrahepatic biliary cystadenoma and cystadenocarcinoma should be considered in differential diagnosis in patients with liver cystic tumors. Because of the high recurrence rate and difficult accurate preoperative diagnosis, formal liver resection is mandatory. Enucleation with free margins is an option and is indicated where resection is impossible.

Neuroendocrine differentiation in embryonal type hepatoblastoma.

Hepatoblastoma, a malignant tumor which arises occasionally in older children but very rarely in adults, exhibits divergent differentiation with embryonal cells, fetal hepatocytes and immature elements. This report describes an embryonal type hepatoblastoma with neuroendocrine differentiation in a 16-year-old patient, which was diagnosed postoperatively. Clinical and radiologic work-up failed to reveal a primary gastrointestinal malignancy and no primary lesions were detected in any other organ. This feature of hepatoblastoma is considered to be a multidirectional differentiation of the small epithelial or stem cells of the liver. At 2-year follow up, the patient remains symptom-free, with normal laboratory and diagnostic imaging studies, and no recurrent or metastatic disease identified.

Extensive tumoral calcinosis in a patient with systemic sclerosis.

Tumoral calcinosis, a rare disease manifesting with periarticular, calcified masses in soft tissues, can be either primary or secondary to a disease, such as systemic sclerosis. In the case reported here, a patient diagnosed with systemic sclerosis presented with hard calcified masses that involved the shoulders and hips.

Iliopsoas: a new electromyographic technique and normal motor unit action potential values.

OBJECTIVE: To describe a reliable technique of needle electrode examination and present the normal values of motor unit action potential (MUAP) parameters in iliopsoas muscle. METHODS: Thirty-one normal subjects underwent quantitative electromyographic (QEMG) examination of the iliopsoas muscle, following an ultrasonographically confirmed technique of needle electrode insertion and sampling. The leg under examination was flexed, abducted and externally rotated at the hip joint and also flexed at the knee joint. A slight flexion at the hip joint was used to uncover iliopsoas from the overlying sartorius. This provides enough space at the inguinal region between the sartorius and the femoral neurovascular bundle. Mean and outlier values of MUAP parameters and polyphasia were calculated. RESULTS: Our technique was easy to perform and secure in sampling iliopsoas. The mean +/- SD values for MUAP duration, amplitude, area, area to amplitude ratio, phases and turns were 11.5 +/- 1.35 ms, 419 +/- 71.5 microV, 633 +/- 142.7 microV ms, 1.57 +/- 0.25, 3.1 +/- 0.32, and 2.9 +/- 0.44, respectively. Lower and upper outlier limits for duration, amplitude, area and area to amplitude ratio were 3.6/20.7 ms, 150/930 microV, 100/1567 microV ms, and 0.35/3.07. Mean polyphasia was 12.6% (range 0-30%). CONCLUSIONS: The suggested EMG technique helped to distinguish iliopsoas from sartorius and at the same time increased the accessibility of its anterior surface. Normal values and outlier limits of the MUAP parameters of iliopsoas have been quantitatively established. SIGNIFICANCE: This new technique and the normal MUAP values might prove helpful for the examination of iliopsoas, important in the assessment of many neuropathic and, especially, myopathic processes.

The effect of contrast media on the synovial membrane.

OBJECTIVE: To examine the effect of intra-articular injection of contrast media, sorbitol and normal saline on the synovial membrane. MATERIALS AND METHODS: Sixty three rabbits (126 knees) were used in this study. We injected the knees with amidotrizoate, ioxaglate, iopamidol, iotrol and diluted gadolinium-DTPA (2 mmol/l). Normal saline and sorbitol 27.25% were used for comparison. A histological and histochemical examination of the knees was carried out 1, 2, 10, 20, 30, 40 and 60 days after the injection. RESULTS: On histological examination, the knees injected with normal saline, ioxaglate and gadolinium-DTPA had a normal appearance. Intra-articular injection of amidotrizoate, iopamidol, iotrol and sorbitol caused early, mild and transient histological changes of the synovium (synovial hyperplasia, infiltration by leucocytes). Furthermore, the knees injected with amidotrizoate presented with late, extensive histological changes (severe synovial hyperplasia, moderate vascular dilatation, severe infiltration by leukocytes). CONCLUSION: The results suggest that the chemical structure and not the osmolality of the contrast media is the main cause for the histological changes of the synovium.