SARS-CoV-2 Related Ischemic Colitis in an Adolescent With Trisomy 21: Diagnostic Pitfalls and Considerations.

Millions of patients seek medical attention for diarrhea, vomiting, nausea, and abdominal pain. In the current environment, it is important to recognize that these symptoms may be the only manifestation or may precede more serious systemic complications of COVID-19. Herein, we describe the first case of ischemic colitis (IC) in a young adult who presented with diarrhea and highlight the laboratory pitfalls for patients with COVID-19 presenting with gastrointestinal (GI) symptoms.

Lexical factors and cerebral regions influencing verbal fluency performance in MCI.

OBJECTIVE: To evaluate assumptions regarding semantic (noun), verb, and letter fluency in mild cognitive impairment (MCI) and Alzheimer disease (AD) using novel techniques for measuring word similarity in fluency lists and a region of interest (ROI) analysis of gray matter correlates. METHOD: Fifty-eight individuals with normal cognition (NC, n=25), MCI (n=23), or AD (n=10) underwent neuropsychological tests, including 10 verbal fluency tasks (three letter tasks [F, A, S], six noun categories [animals, water creatures, fruits and vegetables, tools, vehicles, boats], and verbs). All pairs of words generated by each participant on each task were compared in terms of semantic (meaning), orthographic (spelling), and phonemic (pronunciation) similarity. We used mixed-effects logistic regression to determine which lexical factors were predictive of word adjacency within the lists. Associations between each fluency raw score and gray matter volumes in sixteen ROIs were identified by means of multiple linear regression. We evaluated causal models for both types of analyses to specify the contributions of diagnosis and various mediator variables to the outcomes of word adjacency and fluency raw score. RESULTS: Semantic similarity between words emerged as the strongest predictor of word adjacency for all fluency tasks, including the letter fluency tasks. Semantic similarity mediated the effect of cognitive impairment on word adjacency only for three fluency tasks employing a biological cue. Orthographic similarity was predictive of word adjacency for the A and S tasks, while phonemic similarity was predictive only for the S task and one semantic task (vehicles). The ROI analysis revealed different patterns of correlations among the various fluency tasks, with the most common associations in the right lower temporal and bilateral dorsal frontal regions. Following correction with gray matter volumes from the opposite hemisphere, significant associations persisted for animals, vehicles, and a composite nouns score in the left inferior frontal gyrus, but for letter A, letter S, and a composite FAS score in the right inferior frontal gyrus. These regressions also revealed a lateralized association of the left subcortical nuclei with all letter fluency scores and fruits and vegetables fluency, and an association of the right lower temporal ROI with letter A, FAS, and verb fluency. Gray matter volume in several bihemispheric ROIs (left dorsal frontal, right lower temporal, right occipital, and bilateral mesial temporal) mediated the relationship between cognitive impairment and fluency for fruits and vegetables. Gray matter volume in the right lower temporal ROI mediated the relationship between cognitive impairment and five fluency raw scores (animals, fruits and vegetables, tools, verbs, and the composite nouns score). CONCLUSION: Semantic memory exerts the strongest influence on word adjacency in letter fluency as well as semantic verbal fluency tasks. Orthography is a stronger influence than pronunciation. All types of fluency task raw scores (letter, noun, and verb) correlate with cerebral regions known to support verbal or nonverbal semantic memory. The findings emphasize the contribution of right hemisphere regions to fluency task performance, particularly for verb and letter fluency. The relationship between diagnosis and semantic fluency performance is mediated by semantic similarity of words and by gray matter volume in the right lower temporal region.

Analysis of the oligomeric state and transactivation potential of TAp73α.

The proteins p73 and p63 are members of the p53 protein family and are involved in important developmental processes. Their high sequence identity with the tumor suppressor p53 has suggested that they act as tumor suppressors as well. While p63 has a crucial role in the maintenance of epithelial stem cells and in the quality control of oocytes without a clear role as a tumor suppressor, p73's tumor suppressor activity is well documented. In a recent study we have shown that the transcriptional activity of TAp63α, the isoform responsible for the quality control in oocytes, is regulated by its oligomeric state. The protein forms an inactive, dimeric and compact conformation in resting oocytes, while the detection of DNA damage leads to the formation of an active, tetrameric and open conformation. p73 shows a high sequence identity to p63, including those domains that are crucial in stabilizing its inactive state, thus suggesting that p73's activity might be regulated by its oligomeric state as well. Here, we have investigated the oligomeric state of TAp73α by size exclusion chromatography and detailed domain interaction mapping, and show that in contrast to p63, TAp73α is a constitutive open tetramer. However, its transactivation potential depends on the cellular background and the promoter context. These results imply that the regulation of p73's transcriptional activity might be more closely related to p53 than to p63.

Novel NKX2.1 mutation associated with hypothyroidism and lethal respiratory failure in a full-term neonate.

We report a case of lethal neonatal hypoxic respiratory failure and hypothyroidism in an infant with a novel missense mutation in NKX2.1.

A community-based clinical trial of Intra-Venous zOledRonic acid once Yearly in comparison to oral bisphosphonates in postmenopausal women with osteoporosis: the IVORY trial Methodological considerations.

BACKGROUND: Zoledronic acid is an intravenous once yearly bisphosphonate that has been shown to be effective and safe in improving BMD (bone mineral density) and reducing fracture risk in controlled clinical trials. IVORY is a Canadian post marketing study aiming at assessing real-life effectiveness, health care resource utilization, safety and compliance to treatment with zoledronic acid in comparison to orally administered bisphosphonates (OBP). METHODS: IVORY is a prospective two cohort observational study of patients treated with zoledronic acid or OBP. Eligible patients are postmenopausal females, >45 years old with osteoporosis for whom initiation of treatment with OBP or zoledronic acid is indicated. Subjects will be followed for four years. Outcomes are the change in lumbar spine, femoral neck and total hip BMD and the incidence of fractures. The study cohort will consist of 920 patients treated with zoledronic acid and 460 treated with OBP. Additional comparisons will be based on external standardization to the population of Quebec patients treated with OBP. DISCUSSION: Post Marketing Observational Studies (PMOS) are essential for the assessment of real-life effectiveness and population based benefit-risk ratios. The effect of access to care, compliance, adherence to guidelines, patient comorbidity and concomitant medication use could only be assessed with observational studies. IVORY will provide information about true life effectiveness, benefit-risk ratios, cost-effectiveness and barriers to the process-outcome optimization. The results will have implications for decision makers and health care stakeholders regarding the management of osteoporosis in Canada.

A prospective multicenter phase II study of oral and i.v. vinorelbine plus trastuzumab as first-line therapy in HER2-overexpressing metastatic breast cancer.

BACKGROUND: To evaluate the efficacy and safety of oral and i.v. vinorelbine plus trastuzumab as first-line regimen in a patient-convenient application for human epidermal growth factor receptor 2 (HER2)-overexpressing patients with metastatic breast cancer. PATIENTS AND METHODS: Forty-two women were enrolled in a multicenter study. The patients received i.v. vinorelbine at a dose of 25 mg/m(2) on day 1 followed by oral vinorelbine at a dose of 60 mg/m(2) on days 8 and 15 in a 3-week cycle. Standard dose trastuzumab was given at 3-week intervals. RESULTS: Complete response was observed in 7 patients (18.9%) and partial response in 19 patients (51.4%), for an overall response rate of 70.3% [95% confidence interval (CI) 53.0-84.1]. The disease control rate reached 91.9% (95% CI 78.1-98.3). The median time to progression was 9.3 months, while median overall survival reached 35.6 months. Hematological and non-hematological toxic effects were acceptable with grade 3-4 leukopenia of 14% and neutropenia of 38%; cardiac toxicity did not reach the level of clinical relevance. CONCLUSION: The combination of i.v. and oral vinorelbine plus trastuzumab demonstrates high activity and good tolerability in first-line treatment of HER2-overexpressing metastatic breast cancer. In addition, it offers convenience for the patients with only one i.v. treatment every 3 weeks.

Neural correlates of rapid auditory processing are disrupted in children with developmental dyslexia and ameliorated with training: an fMRI study.

PURPOSE: Developmental dyslexia, characterized by unexpected difficulty in reading, may involve a fundamental deficit in processing rapid acoustic stimuli. Using functional magnetic resonance imaging (fMRI) we previously reported that adults with developmental dyslexia have a disruption in neural response to rapid acoustic stimuli in left prefrontal cortex. Here we examined the neural correlates of rapid auditory processing in children. METHODS: Whole-brain fMRI was performed on twenty-two children with developmental dyslexia and twenty-three typical-reading children while they listened to nonlinguistic acoustic stimuli, with either rapid or slow transitions, designed to mimic the spectro-temporal structure of consonant-vowel-consonant speech syllables. RESULTS: Typical-reading children showed activation for rapid compared to slow transitions in left prefrontal cortex. Children with developmental dyslexia did not show any differential response in these regions to rapid versus slow transitions. After eight weeks of remediation focused primarily on rapid auditory processing, phonological and linguistic training the children with developmental dyslexia showed significant improvements in language and reading skills, and exhibited activation for rapid relative to slow transitions in left prefrontal cortex. CONCLUSION: The presence of a disruption in the neural response to rapid stimuli in children with developmental dyslexia prior to remediation, coupled with significant improvement in language and reading scores and increased brain activation after remediation, gives further support to the importance of rapid auditory processing in reading development and disorders.

A 3-year prospective study of the effects of adjuvant treatments on cognition in women with early stage breast cancer.

The neuropsychological performance of 85 women with early stage breast cancer scheduled for chemotherapy, 43 women scheduled for endocrine therapy and/or radiotherapy and 49 healthy control subjects was assessed at baseline (T1), postchemotherapy (or 6 months) (T2) and at 18 months (T3). Repeated measures analysis found no significant interactions or main effect of group after controlling for age and intelligence. Using a calculation to examine performance at an individual level, reliable decline on multiple tasks was seen in 20% of chemotherapy patients, 26% of nonchemotherapy patients and 18% of controls at T2 (18%, 14 and 11%, respectively, at T3). Patients who had experienced a treatment-induced menopause were more likely to show reliable decline on multiple measures at T2 (OR=2.6, 95% confidence interval (CI) 0.823-8.266 P=0.086). Psychological distress, quality of life measures and self-reported cognitive failures did not impact on objective tests of cognitive function, but were significantly associated with each other. The results show that a few women experienced objective measurable change in their concentration and memory following standard adjuvant therapy, but the majority were either unaffected or even improve over time.

Composition dependence of vesicle morphology and mixing properties in a bacterial model membrane system.

We have determined the mixing properties and lamellar organization of bacterial membrane mimetics composed of 1-palmitoyl-2-oleoyl-phosphatidylethanolamine (POPE) and -phosphatidylglycerol (POPG) at various molar ratios applying differential scanning calorimetry, small and wide-angle X-ray scattering, as well as optical phase contrast microscopy. Combining the experimental thermodynamic data with a simulation of the liquidus and solidus lines, we were able to construct a phase diagram. Using this approach, we find that the lipids mix in all phases non-ideally in the thermodynamic sense. As expected, pure POPE assembles into multilamellar and pure POPG into unilamellar vesicles, respectively, which are stable within the studied temperature range. In contrast, mixtures of the two components form oligolamellar vesicles consisting of about three to five bilayers. The layers within these oligolamellar liposomes are positionally correlated within the gel phase, but become uncorrelated within the fluid phase exhibiting freely fluctuating bilayers, while the vesicles as a whole remain intact and do not break up into unilamellar forms. X-ray, as well as DSC data, respectively, reveal a miscibility gap due to a lateral phase segregation at POPG concentrations above about 70 mol%, similar to previously reported data on mixtures composed of disaturated PEs and PGs. Hence, the existence of a region of immiscibility is a general feature of PE/PG mixtures and the mixing properties are dominated by PE/PG headgroup interactions, but are largely independent of the composition of the hydrocarbon chains. This is in accordance with a recent theoretical prediction.

High efficacy and low toxicity of weekly docetaxel given as first-line treatment for metastatic breast cancer.

BACKGROUND: Docetaxel is one of the most effective antitumor agents currently available for the treatment of metastatic breast cancer (MBC). This phase II multicenter study prospectively analyzed the efficacy and toxicity of docetaxel given on a weekly schedule as first-line treatment of metastatic breast cancer. PATIENTS AND METHODS: All patients received docetaxel, 35 mg/m(2) weekly for 6 weeks, followed by 2 weeks of rest. Subsequent cycles (3 weeks of treatment, 2 weeks of rest) were given until a maximum of 5 cycles or disease progression. Premedication consisted of 8 mg dexamethasone intravenously 30 min prior to the infusion of docetaxel. RESULTS: Fifty-four patients at a median age of 58 years with previously untreated MBC were included in the study. A median of 10 doses (median cumulative dose 339 mg/m(2)) was administered (range: 2-18). The overall response rate was 48.1% (95% CI: 34-61%, intent-to-treat). Median survival was 15.8 months and median time to progression was 5.9 months (intent-to-treat). Hematological toxicity was mild with absence of neutropenia-related complications. Grade 3 neutropenia was observed in 3.7% of patients and grade 3 and 4 anemia was observed in 5.6 and 1.9% of patients, respectively. CONCLUSION: The weekly administration of docetaxel is highly efficient and safe as first-line treatment for MBC and may serve as an important treatment option specifically in elderly patients and patients with a reduced performance status.

The effects of adjuvant chemotherapy on cognition in women with breast cancer--preliminary results of an observational longitudinal study.

Several studies have reported that chemotherapy-treated patients have impaired cognition function relative to control groups. We are conducting a longitudinal study with cognitive assessments at baseline, 6 and 18 months. A planned preliminary analysis of data from 50 chemotherapy patients and 43 healthy controls at baseline and post-treatment found a significant group by time interaction on three measures of verbal and working memory. Chemotherapy patients were more likely to show cognitive decline than controls (OR 2.25). Patients were significantly more likely to have GHQ(12) scores indicative of possible psychological morbidity and showed significant increases in endocrine symptoms and fatigue post-treatment however neither GHQ(12) nor quality-of-life variables were related to cognitive performance.

Transient induction of TGF-alpha disrupts lung morphogenesis, causing pulmonary disease in adulthood.

Clinical studies have associated increased transforming growth factor (TGF)-alpha and EGF receptor with lung remodeling in diseases including bronchopulmonary dysplasia (BPD). BPD is characterized by disrupted alveolar and vascular morphogenesis, inflammation, and remodeling. To determine whether transient increases in TGF-alpha are sufficient to disrupt postnatal lung morphogenesis, we utilized neonatal transgenic mice conditionally expressing TGF-alpha. Expression of TGF-alpha from postnatal days 3 to 5 disrupted postnatal alveologenesis, causing permanent enlargement of distal air spaces in neonatal and adult mice. Lung volume-to-body weight ratios and lung compliance were increased in adult TGF-alpha transgenic mice, whereas tissue and airway elastance were reduced. Elastin fibers in the alveolar septae were fragmented and disorganized. Pulmonary vascular morphogenesis was abnormal in TGF-alpha mice, with attenuated and occasionally tortuous arterial branching. The ratios of right ventricle weight to left ventricle plus septal weight were increased in TGF-alpha mice, indicating pulmonary hypertension. Electron microscopy showed gaps in the capillary endothelium and extravasation of erythrocytes into the alveolar space of TGF-alpha mice. Hemorrhage and inflammatory cells were seen in distal air spaces at 1 mo of age. In adult TGF-alpha mice, alveolar remodeling, nodules, proteinaceous deposits, and inflammatory cells were seen. Immunostaining for pro-surfactant protein C showed that type II cells were abundant in the nodules, as well as neutrophils and macrophages. Trichrome staining showed that pulmonary fibrosis was minimal, apart from areas of nodular remodeling in adult TGF-alpha mice. Transient induction of TGF-alpha during early alveologenesis permanently disrupted lung structure and function and caused chronic lung disease.

Reversal of pulmonary hypertension associated with plexiform lesions in congenital heart disease: a case report.

We describe a 2-year-old child with severe pulmonary hypertension due to a patent ductus arteriosus (PDA) with plexiform lesions on lung biopsy. Despite high basal pulmonary vascular resistance with minimal responsiveness to inhaled nitric oxide and other vasodilators, and advanced plexogenic arteriopathy on lung biopsy, her pulmonary hypertension completely resolved after PDA ligation and during 8 years of follow-up.

Penile cancer: a case for guidelines.

INTRODUCTION: Aspects of the management of penile cancer remain controversial. In the management of early T1 N0 disease, treatments are divided between amputation and a variety of penis conserving techniques (PCT); local excision, laser techniques, chemotherapy and radiotherapy. We report on a retrospective series of patients with penile cancer. PATIENTS AND METHODS: Thirty-seven patients were diagnosed between 1987-1996. All patients records were retrieved. Data recorded included TNM stage, histological grade and treatment. The end-points were death, nodal progression and local recurrence. RESULTS: Median survivor follow-up of 42 months was obtained. Twenty-six patients (70%) presented with T1 disease, 7 (19%) T2 and 4 (11%) T3 or T4. Inguinal nodal disease was seen in 11 (30%). The mean age was 63 years. Overall, 13 penile amputations were performed, 13 underwent radiotherapy, 6 were locally excised in combination with radiotherapy and 3 underwent local excision alone. Two patients were unsuitable for treatment. Of the total (37 patients) 15 have died; 12 from penile cancer. Ten have suffered disease progression and 12 remain alive with no evidence of disease. Twenty-three patients presented with early T1 NO disease. They were treated with radiotherapy (12), local excision (2), combined radiotherapy and excision (2) and partial amputation (4). Outcome was not significantly related to treatment modality. Spread to the inguinal nodes or local recurrence has occurred in 10, of whom 2 have died. Only 13 (57%) appear disease-free. CONCLUSIONS: The characteristics of the patients and the disease in this series are similar to published series in Europe and North America. There is significant variability in the modalities of treatment used within this series. Local recurrence and disease progression occurs in 43% of T1 N0 lesions. There would seem to be some room for improvement. International data are retrospective and inconclusive with regard to best practice. There is an urgent requirement for randomised controlled trials to improve the outcome of these patients.

Navajo neurohepatopathy: a mitochondrial DNA depletion syndrome?

Navajo neurohepatopathy (NNH) is an autosomal recessive disease of full-blooded Navajo children living in the Navajo Reservation of southwestern United States. Clinical features of NNH include peripheral and central nervous system involvement, acral mutilation, corneal scarring or ulceration, liver failure, and metabolic and immunologic derangement. The cause of NNH is unknown, but the clinical features of NNH are similar to those of patients with mitochondrial DNA (mtDNA) depletion. Therefore, we studied mtDNA concentration in the liver from 2 patients with NNH. Using histochemical, biochemical, and molecular techniques, we found evidence of mtDNA depletion, and we propose that the primary defect in NNH is in the nuclear regulation of mtDNA copy number.