A novel approach for the prevention of ionizing radiation-induced bone loss using a designer multifunctional cerium oxide nanozyme.

The disability, mortality and costs due to ionizing radiation (IR)-induced osteoporotic bone fractures are substantial and no effective therapy exists. Ionizing radiation increases cellular oxidative damage, causing an imbalance in bone turnover that is primarily driven via heightened activity of the bone-resorbing osteoclast. We demonstrate that rats exposed to sublethal levels of IR develop fragile, osteoporotic bone. At reactive surface sites, cerium ions have the ability to easily undergo redox cycling: drastically adjusting their electronic configurations and versatile catalytic activities. These properties make cerium oxide nanomaterials fascinating. We show that an engineered artificial nanozyme composed of cerium oxide, and designed to possess a higher fraction of trivalent (Ce3+) surface sites, mitigates the IR-induced loss in bone area, bone architecture, and strength. These investigations also demonstrate that our nanozyme furnishes several mechanistic avenues of protection and selectively targets highly damaging reactive oxygen species, protecting the rats against IR-induced DNA damage, cellular senescence, and elevated osteoclastic activity in vitro and in vivo. Further, we reveal that our nanozyme is a previously unreported key regulator of osteoclast formation derived from macrophages while also directly targeting bone progenitor cells, favoring new bone formation despite its exposure to harmful levels of IR in vitro. These findings open a new approach for the specific prevention of IR-induced bone loss using synthesis-mediated designer multifunctional nanomaterials.

Unusual osteolitic intraosseous ganglion cyst of the medial tibial condyle in a patient affected by mild osteoarthritis of the knee.

Bone lesion of the proximal tibia are common findings; depending on the site, age of the patient and symptoms a carefull differential diagnosis must be carried out. We present the case of  a 60 years old active patient presenting at our clinic with atraumatic  knee pain. X-Rays performed revealed an osteolitic lesion of the medial tibial condyle; MRI  highlighted a lobulated cystic lesion of the medial tibial condyle without evidence of interruption of the suchondral bone. The cavity appeared with low signal intensity on T1 weighted images and with a high signal intensity on T2 images  The tissue obtained from the incisional biopsy macroscopically revealed a clear, yellowish gelatinous and mucinous material; the microscopical hystological exam confirmed a cystic area of the lesion; the lumen contained some dense, fibrous matherial with focal mucoid degeneration, while the wall  was composed of a fibrous tissue with rare ossification and calcification.  Clinical history, imaging and histhological findings lead to a certain diagnosis of an intraosseous ganglion cyst. We decided to surgically treat the lesion with courettage and bone grafting with allograft;the anterior part of the deep medial collateral ligament was used to avoid the leakage of the transplanted bone. With limitations concerning the short follow up, we obtained an optimal result in terms of patients satisfaction; this result is mainly related to the relief of the pain and the possibility for the patient to return to his activities. An accurate follow up must be carried out to verify the integration of the allograft.

Prediction Model for the Presence of Complications at Admission to Rehabilitation After Traumatic Spinal Cord Injury.

Background: Complications frequently occur in patients with spinal cord injury (SCI) during acute care or rehabilitation and have an impact on rehabilitation outcomes. Purpose: The aim of this study was to determine the occurrence and risk factors for complications in recently injured SCI patients. Methods: Two hundred fifty patients with traumatic injuries with and without complications were counted for the following dichotomous parameters: gender (male/female), associated lesions (presence/absence), surgery (yes/no), American Spinal Injury Association Impairment Scale (AIS) grade (A/other categories), lesion level (lumbar/other levels), and lesion-to-admission time (less than/longer than 1 month). The odds ratio (OR) and 95% confidence interval were computed for all the parameters that influenced the presence of complications at admission. These factors have been included in a binary logistic regression analysis (forward stepwise). Results: Complications at admission were observed in 104 patients (41.6%), especially for males, lesion-to-admission time longer than 1 month, presence of associated lesions, AIS grade A, and motor completeness, whereas lumbar lesions were associated with a reduced presence of complications at admission. In the regression analysis, 4 factors entered into the model: motor completeness, lesion-to-admission time, associated lesions, and gender. The final model explained 74% of the variance of data. Conclusions: Despite advances in the acute management of patients with SCI, the study unveiled a high percentage of patients with complications at admission to rehabilitation. The risk factors identified in the study allow determination of the population of subjects who are at higher risk of developing complications and need special management.

Unusual case of hypotenar Hammer Syndrome and carpal tunnel syndrome association.

BACKGROUND AND AIM OF THE WORK: Hypothenar Hammer Syndrome is a relatively rare disease process caused by repetitive stress or injury to the hypothenar eminence leading to chronic injury to the ulnar artery. Our study reports an unusual case. METHODS: A 57 years old Plumber presented in April 2016 with a history of constant pain and recurrent paresthesia involving the fingers of the right hand for several months, over the previous 1 year, his hand had become more intolerant of exposure to cold temperatures. Angio-RNM and electromyography were performed and showed a severe double compression of ulnar and median nerve and an ulnar artery deformity without thrombosis. Surgery was performed under sedation and axillary anesthesia. RESULTS: After surgery patient' symptoms immediately improved, and within a few months, his hand had normalized. CONCLUSION: Hypothenar Hammer Syndrome is a rare disease process which manifests in certain occupations and activities that put undue stress on the hypothenar area. Furthermore, the carpal tunnel syndrome, a pressure damage of the median nerve, caused by repetitive manual tasks with flexion and extension of wrist has been added as well as hypothenar hammer syndrome which are vascular damages of hand caused by shock-type application of force.

Atraumatic acute bilateral quadriceps tendon rupture in a patient with bilateral patella spurs. A case report and review of literature.

BACKGROUND AND AIM OF THE WORK: the spontaneous and simultaneous rupture of both quadriceps tendons is uncommon and has rarely been reported in medical literature. The current case involves a 62-years old man with bilateral atraumatic complete quadriceps tendon rupture. Aim of this study is to provide a systematic review of this case and a literature review of similar cases. Methods: we reviewed and analyzed this patient's records. Initial x rays of both knees showed a bilateral patellar spur. Real time ultrasonography scan of both knees showed a complete tear of quadriceps. The repair has consisted on end to end Krackow sutures associated with bone suture to the proximal pole of the patella using patellar drill holes. We also researched the literature for bilateral simultaneous rupture of the quadriceps tendon. Results: The patient suffered only from seasonal asthma (receiving only inhaled corticosteroids) and he was overweight (BMI: 33,5), he did not do any type of sport, he was a biker. The patient was able to walk after 3 weeks with both knee cast. The patients had a 120° pain free range of motion in both knees 4 months after surgery. Conclusion: Simultaneous bilateral quadriceps tendon rupture is really very rare and these are generally reported as case presentation in the literature. This injury usually presents in middle aged people with a history of chronic illness. The general recommendation is to perform surgical intervention within 48-72 hours after injury.

A Delayed Formation of Pretibial Pseudocyst After Anterior Cruciate Reconstruction from Bioabsorbable Interference Screws: A Report of Two Cases and Short Review of the Literature.

We report two cases of subcutaneous pretibial pseudocyst formation after 7 and 10 years of successful anterior cruciate ligament reconstruction with poly-L-Lactide acid bioabsorbable interference screw fixation with autologous hamstring graft. Both patients underwent surgical excision of the lesion and curettage of the tibial tunnel aperture. The screw had undergone complete resorption at the time the cyst occurred. There was no communication between the tunnel aperture and the knee joint. Both patients had an uneventful recovery returning to their preinjury activity level. Histologic analysis revealed foreign body reaction to the crystalline fractions of the bioabsorbable material with aggregated histiocytes. To our knowledge, this is the first case report describing a delayed formation of pretibial pseudocyst after anterior cruciate reconstruction with bioabsorbable interference screw.

Optoelectronic plethysmography to evaluate the effect of posture on breathing kinematics in spinal cord injury: a cross sectional study.

BACKGROUND: Spinal cord injured patients often suffer from respiratory muscles impairment. Spirometry studies showed that in supine position vital capacity increases in such patients since diaphragm increases its inspiratory excursion. To our opinion, however, respiratory kinematics in spinal cord injured patients is disadvantaged in supine position. AIM: To evaluate the effect of posture (sitting and supine) on respiratory kinematics in chronic spinal cord injured patients using optoelectronic plethysmography. DESIGN: Cross-sectional study. SETTING: Outpatients referring to the Movement Analysis Laboratory of a Physical and Rehabilitation Medicine Unit. POPULATION: Twenty chronic spinal cord injured patients (9 tetraplegics, with lesional level ranging from C3 to C7 and 11 paraplegics with lesional level ranging from T1 to T8) and twenty healthy subjects matched for gender, age and smoking habits. METHODS: All subjects underwent optoelectronic evaluation in sitting and supine position during quiet breathing and hyperventilation. Additional trials were performed to derive respiratory functional parameters (vital capacity and forced expiratory volume in the first second) in sitting and in supine position. Compartmental volumes and respiratory functional parameters were analyzed by means of analysis of variance. Post-hoc comparisons by means of t-tests were performed to analyze differences within and between study groups (spinal cord injured patients and healthy subjects, paraplegics and tetraplegics). Phase angle analysis and Konno and Mead diagrams were performed to evaluate if thoracic and abdominal compartments were moving in synchrony during breathing and the results were compared by paired t-tests. RESULTS: Supine position increases vital capacity and forced expiratory volume in the first second. This could be due to the more favorable length of the diaphragm in supine than in sitting position. However in such posture the phase shift between thorax and abdomen during breathing increases. CONCLUSION: Optoelectronic plethysmography measurements showed that even if in supine position there is an improvement in respiratory functional parameters, the respiratory kinematics of the chest wall is disadvantaged. CLINICAL REHABILITATION IMPACT: Our study suggests that the use of abdominal binders could reproduce in sitting position the positive effect of supine position on diaphragm, that could work at a more favorable point of its length tension curve.

Epigenetic regulation of embryonic stem cell marker miR302C in human chondrosarcoma as determinant of antiproliferative activity of proline-rich polypeptide 1.

Metastatic chondrosarcoma of mesenchymal origin is the second most common bone malignancy and does not respond either to chemotherapy or radiation; therefore, the search for new therapies is relevant and urgent. We described recently that tumor growth inhibiting cytostatic proline-rich polypeptide 1, (PRP-1) significantly upregulated tumor suppressor miRNAs, downregulated onco-miRNAs in human chondrosarcoma JJ012 cell line, compared to chondrocytes culture. In this study we hypothesized the existence and regulation of a functional marker in cancer stem cells, correlated to peptides antiproliferative activity. Experimental results indicated that among significantly downregulated miRNA after PRP-1treatment was miRNAs 302c*. This miRNA is a part of the cluster miR302­367, which is stemness regulator in human embryonic stem cells and in certain tumors, but is not expressed in adult hMSCs and normal tissues. PRP-1 had strong inhibitory effect on viability of chondrosarcoma and multilineage induced multipotent adult cells (embryonic primitive cell type). Unlike chondrosarcoma, in glioblastoma, PRP-1 does not have any inhibitory activity on cell proliferation, because in glioblastoma miR-302-367 cluster plays an opposite role, its expression is sufficient to suppress the stemness inducing properties. The observed correlation between the antiproliferative activity of PRP-1 and its action on downregulation of miR302c explains the peptides opposite effects on the upregulation of proliferation of adult mesenchymal stem cells, and the inhibition of the proliferation of human bone giant-cell tumor stromal cells, reported earlier. PRP-1 substantially downregulated the miR302c targets, the stemness markers Nanog, c-Myc and polycomb protein Bmi-1. miR302c expression is induced by JMJD2-mediated H3K9me2 demethylase activity in its promoter region. JMJD2 was reported to be a positive regulator for Nanog. Our experimental results proved that PRP-1 strongly inhibited H3K9 activity comprised of a pool of JMJD1 and JMJD2. We conclude that inhibition of H3K9 activity by PRP-1 leads to downregulation of miR302c and its targets, defining the PRP-1 antiproliferative role.

Activation of type-2 cannabinoid receptor inhibits neuroprotective and antiinflammatory actions of glucocorticoid receptor α: when one is better than two.

Endocannabinoids (eCBs) and glucocorticoids (GCs) are two distinct classes of signaling lipids that exert both neuroprotective and immunosuppressive effects; however, the possibility of an actual interaction of their receptors [i.e., type-2 cannabinoid (CB2) and glucocorticoid receptor α (GRα), respectively] remains unexplored. Here, we demonstrate that the concomitant activation of CB2 and GRα abolishes the neuroprotective effects induced by each receptor on central neurons and on glial cells in animal models of remote cell death. We also show that the ability of eCBs and GCs, used individually, to inhibit tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) production from activated human T lymphocytes is lost when CB2 and GRα are activated simultaneously. In addition, signal transduction pathways triggered by concomitant activation of both receptors led to increased levels of GRß, heat-shock proteins-70 and -90, and p-JNK, as well as to reduced levels of p-STAT6. These effects were reversed only by selectively antagonizing CB2, but not GRα. Overall, our study demonstrates for the first time the existence of a CB2-driven negative cross-talk between eCB and GC signaling in both rats and humans, thus paving the way to the possible therapeutic exploitation of CB2 as a new target for chronic inflammatory and neurodegenerative diseases.

Selective CB2 receptor agonism protects central neurons from remote axotomy-induced apoptosis through the PI3K/Akt pathway.

Endocannabinoids are neuroprotective in vivo and in vitro, but the mechanisms by which they act are largely unknown. The present study addressed the role of cannabinoid receptors during remote cell death of central neurons in a model that is based on cerebellar lesions. A lesion in one cerebellar hemisphere induced remote cell death and type 2 cannabinoid receptor (CB2R) expression in contralateral precerebellar neurons. Of the selective agonists and antagonists that modulated cannabinoid receptor activity, we found that the CB2R agonist JWH-015 reduced neuronal loss and cytochrome-c release, leading to neurological recovery; these effects were reversed by the selective CB2R antagonist SR144528. Analysis of CB2R-triggered signal transduction demonstrated that in axotomized neurons, CB2R regulated Akt and JNK phosphorylation through a PI3K-dependent pathway, whereas other major signaling routes that are dependent on CB2R, such as ERK1/2 and p38, were not involved. This result was corroborated by the observation that the selective PI3K inhibitor LY294002 blocked the CB2R stimulation effects on neuronal survival as well as Akt and JNK phosphorylation levels. Together, these data demonstrate that axonal damage induces CB2R expression in central neurons and that stimulation of this receptor has a neuroprotective effect that is achieved through PI3K/Akt signaling.

Dendritic LSm1/CBP80-mRNPs mark the early steps of transport commitment and translational control.

Messenger RNA (mRNA) transport to neuronal dendrites is crucial for synaptic plasticity, but little is known of assembly or translational regulation of dendritic messenger ribonucleoproteins (mRNPs). Here we characterize a novel mRNP complex that is found in neuronal dendrites throughout the central nervous system and in some axonal processes of the spinal cord. The complex is characterized by the LSm1 protein, which so far has been implicated in mRNA degradation in nonneuronal cells. In brain, it associates with intact mRNAs. Interestingly, the LSm1-mRNPs contain the cap-binding protein CBP80 that associates with (pre)mRNAs in the nucleus, suggesting that the dendritic LSm1 complex has been assembled in the nucleus. In support of this notion, neuronal LSm1 is partially nuclear and inhibition of mRNA synthesis increases its nuclear localization. Importantly, CBP80 is also present in the dendrites and both LSm1 and CBP80 shift significantly into the spines upon stimulation of glutamergic receptors, suggesting that these mRNPs are translationally activated and contribute to the regulated local protein synthesis.

Inflammatory myelopathies and traumatic spinal cord lesions: comparison of functional and neurological outcomes.

BACKGROUND AND PURPOSE: Outcomes knowledge is essential to answer patients' questions regarding function, to plan the use of resources, and to evaluate treatments to enhance recovery. The purpose of this study was to compare the outcomes of patients with traumatic spinal cord injury (SCI) with those of patients with inflammatory spinal cord lesions (ISCLs). SUBJECTS AND METHODS: The authors evaluated 181 subjects with traumatic SCI and 67 subjects with ISCLs. Using a matching cohorts procedure, 38 subjects were selected from each group. The measures used were the American Spinal Injury Association (ASIA) Impairment Scale (motor function), the Barthel Index (BI), the Rivermead Mobility Index (RMI), and the Walking Index for Spinal Cord Injury (WISCI). RESULTS: The subjects in the ISCL group were older than those in the SCI group, with a longer interval from onset of lesion to rehabilitation admission and more incomplete lesions. In the matching cohorts, at admission, the traumatic SCI group had RMI and WISCI scores comparable to those of the ISCL group, but the traumatic SCI group had lower scores on the BI (greater dependence on assistance for activities of daily living). At discharge, the 2 groups had comparable functional outcomes. The neurological status of the 2 groups was comparable at admission and discharge. DISCUSSION AND CONCLUSION: The results indicate that, at admission, patients with SCI have a greater physical dependence for assistance with activities of daily living than patients with ISCLs who have comparable neurological status. Such a difference depends on factors not related to the spinal cord lesion, such as the presence of associated lesions, the need to wear an orthotic device, or the sequelae of surgery. The outcomes of patients with SCI are determined more by factors such as lesion level and severity and age than by etiology. This finding could have implications for health care planning and rehabilitation research.

P2X2R purinergic receptor subunit mRNA and protein are expressed by all hypothalamic hypocretin/orexin neurons.

Neurophysiologic data suggest that orexin neurons are directly excited by ATP through purinergic receptors (P2XR). Anatomical studies, though reporting P2XR in the hypothalamus, did not describe it in the perifornical hypothalamic area, where orexinergic neurons are located. Here we report the presence of the P2X(2)R subunit in the rat perifornical hypothalamus and demonstrate that hypothalamic orexin neurons express the P2X(2)R. Double immunohistochemistry showed that virtually all orexin-immunoreactive neurons are also P2X(2)R immunoreactive, whereas 80% of P2X(2)R-immunoreactive neurons are also orexin positive. Triple-labeling experiments, combining fluorescence in situ hybridization for P2X(2)R mRNA and P2X(2)R/orexin double immunofluorescence, confirmed these findings. In addition, in situ hybridization demonstrated that P2X(2)R mRNA is localized in cellular processes of orexinergic neurons. The present data support neurophysiologic findings on ATP modulation of orexinergic function and provide direct evidence that the entire population of orexin neurons expresses a P2XR subtype, namely, P2X(2)R. Thus, purinergic transmission might intervene in modulating key functions known to be controlled by the orexinergic system, such as feeding behavior and arousal.