Bone Mineral Density Accrual Determines Energy Expenditure with Refeeding in Anorexia Nervosa and Supersedes Return of Menses

Osteopenia and osteoporosis are major complications of anorexia nervosa (AN). Since bone is a tissue requiring large amounts of energy, we examined the disproportionate increase in resting energy expenditure (REE) that occurs with refeeding of AN patients to determine if it was related to bone accretion. Thirty-seven AN patients aged 23.4 ± 4.8 years underwent a behavioral weight-gain protocol lasting a median of 66 days; 27 remained amenorrheic, and 10 regained menses. Sixteen controls aged 25.1 ± 4.7 years were age- and % IBW matched with patients. REE was measured using a respiratory chamber-indirect calorimeter. Significant correlations were found between REE and changes in spine (r = 0.48, P < 0.02) and leg (r = 0.43, P < 0.05) BMDs in AN patients. Further subgroup analysis of the amenorrheics revealed significant correlation between REE and change in spine BMD (r = 0.59, P < 0.02) and higher IGF-1 after weight gain compared to controls. Amenorrheics also had lower BMDs. These findings were absent in the regained menses group. The increase in REE seen in women with AN during nutritional rehabilitation may be related to active bone formation, which is not as prominent when menses have returned

Functional magnetic resonance imaging in primary hyperparathyroidism

Objective: The neurophysiological mechanisms underlying cognitive dysfunction in primary hyperparathyroidism (PHPT) and the brain regions affected are not clear. We assessed neural activation during cognitive testing (matrix reasoning, paired associates, and logical memory) using functional MRI (fMRI) in 23 patients with PHPT and 23 healthy controls. A subset with PHPT was re-assessed 6 months post-parathyroidectomy (PTX). Design: This is an observational study comparing neural activation by fMRI in patients with PHPT to normative controls. Postmenopausal women were studied at a tertiary referral center. Results: There were no between-group differences in cognitive task performance. Patients with PHPT had lower neural activation vs controls (max Z = 4.02, all P < 0.01) during matrix reasoning in brain regions involved in executive function (left frontal lobe (k = 57) and right medial frontal gyrus (k = 72)) and motor function (right precentral gyrus (k = 51)). During paired associates (verbal memory), those with PHPT had greater activation in the right inferior parietal lobule (language/mathematical operations; k = 65, P < 0.01). Greater activation in this region bilaterally correlated with higher PTH (k = 96, P < 0.01). Post-PTX, activation decreased during matrix reasoning, but in different regions than those affected pre-PTX. Conclusions: PHPT is associated with differences in task-related neural activation patterns, but no difference in cognitive performance. While this may indicate compensation to maintain the same cognitive function, there was no clear improvement in neural activation after PTX. Larger, longitudinal studies that include PHPT patients followed without surgery are needed to determine if PTX could prevent worsening of altered neural activation patterns in PHPT

Identification of BRCA1 missense substitutions that confer partial functional activity: potential moderate risk variants?

Introduction: Many of the DNA sequence variants identified in the breast cancer susceptibility gene BRCA1 remain unclassified in terms of their potential pathogenicity. Both multifactorial likelihood analysis and functional approaches have been proposed as a means to elucidate likely clinical significance of such variants, but analysis of the comparative value of these methods for classifying all sequence variants has been limited. Methods: We have compared the results from multifactorial likelihood analysis with those from several functional analyses for the four BRCA1 sequence variants A1708E, G1738R, R1699Q, and A1708V. Results: Our results show that multifactorial likelihood analysis, which incorporates sequence conservation, co-inheritance, segregation, and tumour immunohistochemical analysis, may improve classification of variants. For A1708E, previously shown to be functionally compromised, analysis of oestrogen receptor, cytokeratin 5/6, and cytokeratin 14 tumour expression data significantly strengthened the prediction of pathogenicity, giving a posterior probability of pathogenicity of 99%. For G1738R, shown to be functionally defective in this study, immunohistochemistry analysis confirmed previous findings of inconsistent 'BRCA1-like' phenotypes for the two tumours studied, and the posterior probability for this variant was 96%. The posterior probabilities of R1699Q and A1708V were 54% and 69%, respectively, only moderately suggestive of increased risk. Interestingly, results from functional analyses suggest that both of these variants have only partial functional activity. R1699Q was defective in foci formation in response to DNA damage and displayed intermediate transcriptional transactivation activity but showed no evidence for centrosome amplification. In contrast, A1708V displayed an intermediate transcriptional transactivation activity and a normal foci formation response in response to DNA damage but induced centrosome amplification. Conclusion: These data highlight the need for a range of functional studies to be performed in order to identify variants with partially compromised function. The results also raise the possibility that A1708V and R1699Q may be associated with a low or moderate risk of cancer. While data pooling strategies may provide more information for multifactorial analysis to improve the interpretation of the clinical significance of these variants, it is likely that the development of current multifactorial likelihood approaches and the consideration of alternative statistical approaches will be needed to determine whether these individually rare variants do confer a low or moderate risk of breast cancer

The Small GTPase RhoA Localizes to the Nucleus and Is Activated by Net1 and DNA Damage Signals

Rho GTPases control many cellular processes, including cell survival, gene expression and migration. Rho proteins reside mainly in the cytosol and are targeted to the plasma membrane (PM) upon specific activation by guanine nucleotide exchange factors (GEFs). Accordingly, most GEFs are also cytosolic or associated with the PM. However, Net1, a RhoA-specific GEF predominantly localizes to the cell nucleus at steady-state. Nuclear localization for Net1 has been seen as a mechanism for sequestering the GEF away from RhoA, effectively rendering the protein inactive. However, considering the prominence of nuclear Net1 and the fact that a biological stimulus that promotes Net1 translocation out the nucleus to the cytosol has yet to be discovered, we hypothesized that Net1 might have a previously unidentified function in the nucleus of cells.Using an affinity precipitation method to pulldown the active form of Rho GEFs from different cellular fractions, we show here that nuclear Net1 does in fact exist in an active form, contrary to previous expectations. We further demonstrate that a fraction of RhoA resides in the nucleus, and can also be found in a GTP-bound active form and that Net1 plays a role in the activation of nuclear RhoA. In addition, we show that ionizing radiation (IR) specifically promotes the activation of the nuclear pool of RhoA in a Net1-dependent manner, while the cytoplasmic activity remains unchanged. Surprisingly, irradiating isolated nuclei alone also increases nuclear RhoA activity via Net1, suggesting that all the signals required for IR-induced nuclear RhoA signaling are contained within the nucleus.These results demonstrate the existence of a functional Net1/RhoA signaling pathway within the nucleus of the cell and implicate them in the DNA damage response

Pitfall in the Diagnosis of Diabetes Insipidus and Pregnancy

Diabetes insipidus (DI) during pregnancy and the perinatal period is an uncommon medical problem characterized by polyuria and excessive thirst. Diagnosis of DI may be overlooked in the setting of pregnancy, a time when increased water intake and urine output are commonly reported. We report two cases: one of transient DI in a young woman during her third trimester of twin pregnancy in association with acute fatty liver and hypertension and one of postpartum DI secondary to Sheehan syndrome from rupture of a splenic artery aneurysm. These cases illustrate the spectrum with which DI related to pregnancy and delivery can present and highlight the difficulty in making the diagnosis since the symptoms are often initially overlooked

Clinical and Diffusion Tensor MRI Findings in Congenital Homonymous Hemianopia

A 29-year-old woman underwent brain MRI for increasing frequency of migraine headaches. The MRI report recommended further evaluation for septo-optic dysplasia. The patient reported no visual deficits. Her examination showed normal visual acuities, color vision, pupillary function, and a normal optic disc in the right eye with mild temporal disc pallor in the left eye. Automated perimetry revealed an incongruous left homonymous hemianopia (Fig. 1). Optical coherence tomography (OCT) showed thinning of the retinal nerve fiber layer to 60 µm in the right eye and 54 µm in the left eye. There was ganglion cell layer thinning in a hemianopic pattern with temporal thinning in the right eye and nasal thinning in the left eye. This corresponded with the left homonymous hemianopia

Cross-lagged Relationships among Interpersonal Closeness, Early Language Skills, and Emotion Understanding in Toddlers

This longitudinal study examined how parent-child closeness, teacher-child closeness, and language skills predicted and were predicted by emotion understanding in early years. Participants were 128 Hong-Kong-Chinese toddlers (74 girls; Mage = 33.03 months). Parents and teachers reported their closeness with each child, and children’s oral language and emotion understanding were tested at two timepoints six months apart. Cross-lagged modeling analyses showed a unidirectional link from parent-child closeness predicting emotion understanding, a unidirectional link from emotion understanding predicting teacher-child closeness, and a bidirectional relation between oral language and emotion understanding. This study connects children’s emotion understanding with their own characteristics and their social relationships in the family and classroom settings, providing a fuller picture of early emotional development across multiple contexts