A conserved myotubularin-related phosphatase regulates autophagy by maintaining autophagic flux.

Macroautophagy (autophagy) targets cytoplasmic cargoes to the lysosome for degradation. Like all vesicle trafficking, autophagy relies on phosphoinositide identity, concentration, and localization to execute multiple steps in this catabolic process. Here, we screen for phosphoinositide phosphatases that influence autophagy in Drosophila and identify CG3530. CG3530 is homologous to the human MTMR6 subfamily of myotubularin-related 3-phosphatases, and therefore, we named it dMtmr6. dMtmr6, which is required for development and viability in Drosophila, functions as a regulator of autophagic flux in multiple Drosophila cell types. The MTMR6 family member MTMR8 has a similar function in autophagy of higher animal cells. Decreased dMtmr6 and MTMR8 function results in autophagic vesicle accumulation and influences endolysosomal homeostasis.

Autophagy in animal development.

Macroautophagy (autophagy) delivers intracellular constituents to the lysosome to promote catabolism. During development in multiple organisms, autophagy mediates various cellular processes, including survival during starvation, programmed cell death, phagocytosis, organelle elimination, and miRNA regulation. Our current understanding of autophagy has been enhanced by developmental biology research during the last quarter of a century. Through experiments that focus on animal development, fundamental mechanisms that control autophagy and that contribute to disease were elucidated. Studies in embryos revealed specific autophagy molecules that mediate the removal of paternally derived mitochondria, and identified autophagy components that clear protein aggregates during development. Importantly, defects in mtDNA inheritance, or removal of paternal mtDNA via mitochondrial autophagy, can contribute to mitochondrial-associated disease. In addition, impairment of the clearance of protein aggregates by autophagy underlies neurodegenerative diseases. Experiments in multiple organisms also reveal conserved mechanisms of tissue remodeling that rely on the cooperation between autophagy and apoptosis to clear cell corpses, and defects in autophagy and apoptotic cell clearance can contribute to inflammation and autoimmunity. Here we provide an overview of key developmental processes that are mediated by autophagy in multiple animals.

Hip-ankle coordination during gait in individuals with chronic ankle instability.

Individuals with chronic ankle instability (CAI) may have sensorimotor impairments that affect control at the hip in addition to the ankle. The purpose of this study was to compare hip-ankle coordination and coordination variability between individuals with CAI and healthy individuals during walking. Ten healthy subjects and 10 subjects with CAI were recruited to walk on a treadmill. Hip-ankle coordination was quantified using vector coding, and coordination variability was quantified using coefficient of correspondence. We found significant between-group differences in hip-ankle coordination in the frontal plane around loading response (Control: 165.9±18.4°; CAI: 127.6±48.6°, p=0.04) and in the sagittal plane around the first half of mid stance (Control: 307.2±9.8°; CAI: 291.8±11.4°, p<0.01), terminal stance (Control: 301.1±13°; CAI: 313.4±10.9°, p=0.04), and pre-swing (Control: 243.9±35.2°; CAI: 329.9±57.8°, p<0.01). We also found significant between-group differences in hip-ankle coordination variability in the frontal plane around the second half of mid stance (Control: 0.54±0.06; CAI: 0.45±0.07, P<0.01). CAI is associated with alteration of hip-ankle coordination and coordination variability in stance phase during walking. Gait training is important in CAI rehabilitation, and the training should address altered hip-ankle coordination to reduce the risk of recurrent injuries.

Melanoma with gastric metastases.

An 81-year-old woman with a history of malignant melanoma who presented with dyspnea and fatigue was found to have metastases to the stomach detected on endoscopy. Primary cutaneous malignant melanoma with gastric metastases is a rare occurrence, and it is often not detected until autopsy because of its non-specific manifestations.

Chondrocyte Viability 3.5 Years Following a Vascularized Medial Femoral Trochlea Osteocartilaginous Free Flap.

CASE: A 30-year-old woman underwent arthroscopy for wrist pain 3.5 years following a medial femoral trochlea (MFT) osteocartilaginous free flap for Kienböck disease, which provided the opportunity to examine the transferred cartilage in vivo. Arthroscopy revealed no evidence of chondrolysis, and histologic examination revealed uniformly viable chondrocytes within a matrix consistent with fibrocartilage. CONCLUSION: To the best of our knowledge, the long-term viability of chondrocytes following an MFT free flap has not been previously documented. This case provides early evidence that free tissue transfer based on the descending genicular artery can provide a durable solution for osteocartilaginous defects.

Nkx2.1-derived astrocytes and neurons together with Slit2 are indispensable for anterior commissure formation.

Guidepost cells present at and surrounding the midline provide guidance cues that orient the growing axons through commissures. Here we show that the transcription factor Nkx2.1 known to control the specification of GABAergic interneurons also regulates the differentiation of astroglia and polydendrocytes within the mouse anterior commissure (AC). Nkx2.1-positive glia were found to originate from three germinal regions of the ventral telencephalon. Nkx2.1-derived glia were observed in and around the AC region by E14.5. Thereafter, a selective cell ablation strategy showed a synergistic role of Nkx2.1-derived cells, both GABAergic interneurons and astroglia, towards the proper formation of the AC. Finally, our results reveal that the Nkx2.1-regulated cells mediate AC axon guidance through the expression of the repellent cue, Slit2. These results bring forth interesting insights about the spatial and temporal origin of midline telencephalic glia, and highlight the importance of neurons and astroglia towards the formation of midline commissures.

Cytopathologic findings in breast masses in men with HIV infection.

OBJECTIVE: To report the cytologic findings on 15 men with HIV infection who presented with breast masses and underwent fine needle aspiration (FNA). STUDY DESIGN: The cytopathology files of The Johns Hopkins Hospital (JHH) and the University of Texas Southwestern Medical Center (UTSW) were searched for cases of men with breast masses evaluated by FNA. The HIV status of these men was then ascertained. A total of 15 cases (9 at JHH, 6 at UTSW) of 259 (5.79%) were identified in which the patient was HIV seropositive. The pathologic diagnoses were reviewed, and the clinical history, along with the medication list at the time of FNA, was determined. RESULTS: The men ranged in age from 12 to 51 years (mean, 38). Breast masses were present on either the right (n = 6) or left (n = 7) side or were bilateral (n = 2). In all 15 cases, the masses were retroareolar, firm and tender. FNA showed a ductal and stromal proliferative process, often with focal cytologic atypia and numerous background naked myoepithelial nuclei, features consistent with a diagnosis of gynecomastia. Thirteen of these men were on drug regimens, which included indinivir, stavudine and saquinivir. Two of the men were on azidothymidine only. CONCLUSION: Gynecomastia, although rare in young men, was the sole cause of breast masses in HIV-seropositive men in this study. It has been described as an extremely rare side effect of certain antiretroviral medications, including indinivir, stavudine and saquinivir. FNA is an important tool in determining the benign nature of these lesions and excluding other causes of breast masses in this patient population, such as infections, malignant lymphoma and breast carcinoma.

Multilocular prostatic cystadenoma with high-grade prostatic intraepithelial neoplasia.

Multilocular prostatic cystadenoma is a rarely encountered neoplasm located in the midline between the bladder and rectum that is either attached to the prostate by a pedicle or separate from the prostate entirely. Histologically and immunohistochemically these lesions resemble benign prostate tissue. We report the first case of this entity for which multifocal high-grade prostatic intraepithelial neoplasia (PIN) is identified. Conceptually, the finding of high-grade PIN in multilocular prostatic cystadenomas provides further evidence that these lesions are fully analogous to the prostate gland not only in their morphology and immunohistochemistry but also in their predilection for the same diseases.

Using semantics, grammar, phonology, and rapid naming tasks to predict word identification.

This study investigated the relative importance of semantic, grammatical, phonological, and rapid naming abilities in predicting word identification in a large, representative sample of children enrolled in first through sixth grade, using correlation, factor analysis, multiple regression, and predictive outcome analysis techniques. Composite measures of these abilities were found to correlate significantly with word identification, even after controlling for the effects of nonverbal intelligence. Factor analysis indicated that the spoken language composites and the word identification composite loaded on one factor, whereas the perceptual speed composites loaded on a second factor. Multiple regression analyses showed that among younger children in the early stages of learning to read and children whose word identifying skills were below average, the phonology and rapid naming composites accounted for the most variance in predicting word identification skills. Among older children and children who were proficient in word identification, the semantics composite accounted for the most variance. The most important analyses in this study (i.e., the calculations of the sensitivity indexes, the specificity indexes, and the positive predictive values) evaluated the practical value of using the composites to predict poor word identification skills in children. To be considered practically useful, all predictive outcome values had to be .75 or greater. None of the composites studied, including an application of the double-deficit hypothesis, met this criterion. The results from this study question the accuracy and utility of using any of the abilities studied to predict which students are at risk for or have poor word identification skills.