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Transient global ischemia arising as a consequence of cardiac arrest in humans causes selective, delayed death of hippocampal CA1 pyramidal neurons and cognitive impairment. Effective treatments to ameliorate the neurodegeneration and cognitive dysfunction associated with global ischemia are an unmet need. Emerging evidence points to a widespread role for microRNAs (miRNAs) as key modulators of target gene expression in neurons. Accordingly, dysregulation of miRNAs are implicated in the pathophysiology of neurodegenerative disease and neurological disorders. Our findings, derived via miRNA-seq, indicate that expression of a subset of microRNAs are altered in postischemic CA1 including miR-34b/c, miR-21, miR-331, miR-181 and miR-29. Ingenuity pathway analysis reveals that miR-34b/c is the leading miR candidate implicated in cell death and survival. A role for miR-34 in the pathogenesis of global ischemia is, as yet, unclear. Here we show ischemia induces p53-dependent activation of miR-34b/c and downregulation of its target genes Bcl-2 and Sirt1, which together promote neuronal death in selectively vulnerable hippocampal CA1 in vivo . Consistent with this, inhibition of miR-34b/c affords neuroprotection, rescues impaired synaptic plasticity and reduces memory deficits in global ischemia. These findings document a causal role for p53-dependent activation of miR-34b/c in neuronal death and identify a novel therapeutic target for amelioration of the neurodegeneration and cognitive deficits associated with ischemic stroke.

The mammalian genome pervasively transcribes a variety of functional noncoding transcripts, including the recently discovered long noncoding RNAs (lncRNAs). LncRNAs play major roles in regulating gene expression in mammals, but their expression and functions in the post-stroke brain remain largely unknown. Using a mouse model of transient focal ischemia, we applied RNA-sequencing to evaluate for the first time the unbiased, genome-wide expression of lncRNAs as a function of reperfusion time in the cerebral cortex. A 1h middle cerebral artery occlusion was conducted in adult male mice and ipsilateral cortices were harvested at 6h, 12h or 24h of reperfusion. RNA was isolated and used for Illumina sequencing. The reads were assembled and mapped to mouse reference genome GRCm38/mm10 and differential expression between the groups was evaluated using TopHat-Cufflinks. We observed that the baseline expression of lncRNAs in the healthy cortex was low, but hundreds of lncRNAs were highly altered after stroke. We identified 1311 isoforms at 6h (1146 upregulated; 165 downregulated), 1287 isoforms at 12h (954 upregulated; 333 downregulated), and 1090 isoforms at 24h (907 upregulated; 183 downregulated) of reperfusion that were significantly altered (absolute fold-change ≥ 2; q-value

Nonaccidental trauma (NAT) is most common and most lethal in infants. Falls are the most frequently given explanation for NAT, and head injuries can result from both mechanisms. We hypothesized that infant head injuries from NAT have a distinct injury profile compared to falls.The trauma registry and patient records were reviewed from 2004 to 2008. Infants with at least 1 head computed tomography were included.Ninety-nine infants were identified. Falls (67 patients) and NAT (21 patients) were the most common mechanism of injury. Falls had lower injury severity scores, 5 versus 17 compared to NAT (P0.001). Nonaccidental trauma patients had injuries to face, chest, abdomen, or extremities much more frequently, 62% versus 3% in falls (P0.001). Isolated intracranial hemorrhage was higher in NAT (60% vs. 23%, P = 0.002), whereas isolated skull fracture was higher in falls (42% vs. 5%, P = 0.005). Outcomes for NAT showed longer intensive care unit stays (4 days vs. 1 day; P0.001), longer hospital stays (7 days vs. 1 day; P0.001), and more intracranial operations (9 vs. 1; P0.001).We recommend that all children younger than 1 year, with an isolated intracranial hemorrhage, have a full NAT work-up. Injury severity score greater than 20, Glasgow Coma Scale less than 13, and extracranial injuries should also increase suspicion of NAT.

Mucopolysaccharidosis (MPS) IIIB (Sanfilippo syndrome, OMIM 252920) is a lysosomal storage disorder caused by the deficiency of α-N-acetylglucosaminidase (NAGLU), a lysosomal hydrolase involved in the degradation of heparan sulphate (HS) (1). MPS IIIB is characterized by multisystem involvement and a complex phenotype. The most debilitating manifestations of the disease are those related to central nervous system disease, with severe and progressive mental retardation, hyperactivity, and behavioral problems. Skeletal and visceral manifestations are less prominent, as compared with other MPS. Gastrointestinal manifestations, including diarrhea and constipation, have occasionally been described in patients with MPS IIIB, but they have been poorly characterized and their pathophysiology is not known. Although gastrointestinal symptoms are often overshadowed by the severe neurological phenotype, they may affect the quality of life of patients and of their families. We describe a case of MPS IIIB, referred to our hospital because of chronic diarrhea, in which abnormalities of intestinal endoscopy, histology, and scintigraphy with Tc-99m-labeled human serum albumin were found, partially overlapping with the features of intestinal lymphangiectasia. In this patient, a low-fat diet and supplementation of medium-chain triglycerides were started, leading to persisting improvement of diarrhea. These results add information on the pathophysiology of intestinal manifestations in MPS IIIB patients and possibly in other MPS patients with a history of chronic diarrhea.

Background: Ankle arthrodesis is considered by many to be the standard operative treatment for end-stage ankle arthritis; however, the long-term effect of ankle arthrodesis on other lower-extremity joints remains largely unknown. The purpose of this study was to perform a clinical and radiographic review to determine the effect of ankle arthrodesis on the development of osteoarthritis in other lower-extremity joints. Methods: Twenty-three patients who had had an isolated ankle arthrodesis for the treatment of painful post-traumatic arthritis of the ankle were followed for a mean of twenty-two years (range, twelve to forty-four years) after the operation. Each completed standardized, self-reported outcome questionnaires (the Foot Function Index, Western Ontario and McMaster University Osteoarthritis Index [WOMAC], and Short Form-36 [SF-36]), was examined clinically by two of the investigators, and underwent complete radiographic examination of the knee, ankle, and foot bilaterally. The radiographic grade of osteoarthritis was determined for each joint, and the levels of overall activity limitation, pain, and disability were determined for each patient from the clinical findings and questionnaire information. Results: Osteoarthritis of the ipsilateral subtalar (p < 0.0001), talonavicular (p < 0.0001), calcaneocuboid (p < 0.0001), naviculocuneiform (p = 0.0012), tarsometatarsal (p = 0.0009), and first metatarsophalangeal joints (p = 0.0012) was consistently more severe than the osteoarthritis of those joints on the contralateral side. Osteoarthritis did not develop more frequently in the ipsilateral knee or lesser metatarsophalangeal joints than it did on the contralateral side. Significant differences between the two sides were found with regard to overall activity limitation (p < 0.0001), pain (p < 0.0001), and disability (p < 0.0001), with the involved side consistently more symptomatic. Conclusions: To our knowledge, the present series represents the longest follow-up study of ankle arthrodesis to date. Our cohort of patients all had isolated post-traumatic ankle arthritis, and each underwent a successful isolated ankle arthrodesis. At a mean of twenty-two years, the majority of the patients had substantial, and accelerated, arthritic changes in the ipsilateral foot but not the knee. They were often limited functionally by foot pain. Although ankle arthrodesis may provide good early relief of pain, it is associated with premature deterioration of other joints of the foot and eventual arthritis, pain, and dysfunction.

METHODS: We developed a strain of double transgenic mice carrying a COX-2 gene under control of tetracycline-inducible promoter (TRE-COX-2 transgene) and a reverse tetracycline transcriptional activator gene under control of villin promoter (villinrtTA2-M2 transgene). Single transgenic and wild type animals served as controls. Adult mice were given a doxycycline diet for 48h and were gavaged with 0.44 mg/kg FITC-dextran and 475 mg/kg lactulose. After 16 hours, intestinal, blood, and urine samples were obtained. Serum concentrations of FITC-dextran were determined by fluorometry and urine lactulose was determined by chromatography. Levels of Cox-2 were measured on western blot and tight junctional proteins Jam-A and ZO-1 were evaluated by immunofluorescence.

Twenty-nine of 45 patients who had ipsilateral femoral and tibial shaft fractures were evaluated clinically and roentgenographically to correlate treatment method with bony alignment and functional outcome. The results included: (1) limitation of sports activities in patients whose knee ligaments were injured, followed by both instability and thigh atrophy; (2) a direct relationship between the postunion malalignment of the tibia and ankle motion; and (3) a high rate of life threatening complications (thromboembolic, pneumonia, death) and a slower rate of tibial union associated with treatment by closed methods.

When severe adjacent soft tissue injury precludes early operative repair of the patellar tendon, proximal migration of the patella and secondary quadriceps contracture may occur. Ambulatory dynamic patellar traction employs a cast brace assembly that prevents or corrects early proximal migration of the patella. The cast brace assembly incorporates a transverse threaded Steinmann pin through the patella, wire loops on the leg section of a cast brace, rubber band traction between the Steinmann pin and the wire loops, and drop lock knee hinges. The use of drop lock hinges allows passive knee motion when the lock is released and ambulation with a stable knee when the hinge is locked. Application of the dynamic ambulatory traction method is employed in the case of a 21-year-old man who sustained a severe electrical burn to the knee with loss of anterior soft tissue, including the patellar tendon. The prescribed traction method corrected early proximal migration of the patella prior to infrapatellar tendon reconstruction.