Gamma nail versus percutaneous compression plate for the treatment of intertrochanteric hip fractures: a multicenter pair-matched study.

PURPOSE: To compare functional outcomes, complication rates, and survival in patients with intertrochanteric fracture treated with percutaneous compression plate (PCCP) or gamma nail (GN). METHODS: A retrospective study of prospectively collected data of patients treated with PCCP or GN for AO/OTA 31.A1 or AO/OTA 31.A2 fractures was conducted. Sixty-eight consecutive patients treated with PCCP between 2018 and 2020 were enrolled and matched with 68 patients with comparable characteristics treated with GN. The activities of daily living (ADL) index and specific scales for walking ability and need for walking aids at 4 months and 1 year after fracture fixation were chosen as primary outcomes. Postoperative complications and one-year survival were recorded and compared between the two groups. RESULTS: Walking ability and ADLs index decreased and the need for walking aids increased in both groups compared to the prefracture state at both follow-up intervals (p < 0.001), regardless of the treatment received. There was no difference between the two implants in the rate of implant-related complications. One-year survival rate was 78.9% (95% CI 67.0-86.9) and 82.4% (95% CI 71.0-89.5) in patients undergoing PCCP or GN, respectively, with no significant difference between the two groups. CONCLUSIONS: Walking ability, ADLs, complication rate, and 1-year survival are not significantly different when patients undergoing PCCP or GN are compared. The choice of implant may not be decisive for the outcome of treatment of intertrochanteric fractures, provided that stable fixation is ensured.

Axonal damage in spinal cord is associated with gray matter atrophy in sensorimotor cortex in experimental autoimmune encephalomyelitis.

BACKGROUND: Gray matter (GM) atrophy in brain is one of the best predictors of long-term disability in multiple sclerosis (MS), and recent findings have revealed that localized GM atrophy is associated with clinical disabilities. GM atrophy associated with each disability mapped to a distinct brain region, revealing a disability-specific atlas (DSA) of GM loss. OBJECTIVE: To uncover the mechanisms underlying the development of localized GM atrophy. METHODS: We used voxel-based morphometry (VBM) to evaluate localized GM atrophy and Clear Lipid-exchanged Acrylamide-hybridized Rigid Imaging-compatible Tissue-hYdrogel (CLARITY) to evaluate specific pathologies in mice with experimental autoimmune encephalomyelitis (EAE). RESULTS: We observed extensive GM atrophy throughout the cerebral cortex, with additional foci in the thalamus and caudoputamen, in mice with EAE compared to normal controls. Next, we generated pathology-specific atlases (PSAs), voxelwise mappings of the correlation between specific pathologies and localized GM atrophy. Interestingly, axonal damage (end-bulbs and ovoids) in the spinal cord strongly correlated with GM atrophy in the sensorimotor cortex of the brain. CONCLUSION: The combination of VBM with CLARITY in EAE can localize GM atrophy in brain that is associated with a specific pathology in spinal cord, revealing a PSA of GM loss.

In vivo magnetic resonance images reveal neuroanatomical sex differences through the application of voxel-based morphometry in C57BL/6 mice.

Behaviorally relevant sex differences are often associated with structural differences in the brain and many diseases are sexually dimorphic in prevalence and progression. Characterizing sex differences is imperative to gaining a complete understanding of behavior and disease which will, in turn, allow for a balanced approach to scientific research and the development of therapies. In this study, we generated novel tissue probability maps (TPMs) based on 30 male and 30 female in vivo C57BL/6 mouse brain magnetic resonance images and used voxel-based morphometry (VBM) to analyze sex differences. Females displayed larger anterior hippocampus, basolateral amygdala, and lateral cerebellar cortex volumes, while males exhibited larger cerebral cortex, medial amygdala, and medial cerebellar cortex volumes. Atlas-based morphometry (ABM) revealed a statistically significant sex difference in cortical volume and no difference in whole cerebellar volume. This validated our VBM findings that showed a larger cerebral cortex in male mice and a pattern of dimorphism in the cerebellum where the lateral portion was larger in females and the medial portion was larger in males. These results are consonant with previous ex vivo studies examining sex differences, but also suggest further regions of interest.

Anchoring dipalmitoyl phosphoethanolamine to nanoparticles boosts cellular uptake and fluorine-19 magnetic resonance signal.

Magnetic resonance (MR) methods to detect and quantify fluorine ((19)F) nuclei provide the opportunity to study the fate of cellular transplants in vivo. Cells are typically labeled with (19)F nanoparticles, introduced into living organisms and tracked by (19)F MR methods. Background-free imaging and quantification of cell numbers are amongst the strengths of (19)F MR-based cell tracking but challenges pertaining to signal sensitivity and cell detection exist. In this study we aimed to overcome these limitations by manipulating the aminophospholipid composition of (19)F nanoparticles in order to promote their uptake by dendritic cells (DCs). As critical components of biological membranes, phosphatidylethanolamines (PE) were studied. Both microscopy and MR spectroscopy methods revealed a striking (at least one order of magnitude) increase in cytoplasmic uptake of (19)F nanoparticles in DCs following enrichment with 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine (DPPE). The impact of enriching (19)F nanoparticles with PE on DC migration was also investigated. By manipulating the nanoparticle composition and as a result the cellular uptake we provide here one way of boosting (19)F signal per cell in order to overcome some of the limitations related to (19)F MR signal sensitivity. The boost in signal is ultimately necessary to detect and track cells in vivo.

Enlargement of cerebral ventricles as an early indicator of encephalomyelitis.

Inflammatory disorders of the central nervous system such as multiple sclerosis and acute disseminated encephalomyelitis involve an invasion of immune cells that ultimately leads to white matter demyelination, neurodegeneration and development of neurological symptoms. A clinical diagnosis is often made when neurodegenerative processes are already ongoing. In an attempt to seek early indicators of disease, we studied the temporal and spatial distribution of brain modifications in experimental autoimmune encephalomyelitis (EAE). In a thorough magnetic resonance imaging study performed with EAE mice, we observed significant enlargement of the ventricles prior to disease clinical manifestation and an increase in free water content within the cerebrospinal fluid as demonstrated by changes in T2 relaxation times. The increase in ventricle size was seen in the lateral, third and fourth ventricles. In some EAE mice the ventricle size started returning to normal values during disease remission. In parallel to this macroscopic phenomenon, we studied the temporal evolution of microscopic lesions commonly observed in the cerebellum also starting prior to disease onset. Our data suggest that changes in ventricle size during the early stages of brain inflammation could be an early indicator of the events preceding neurological disease and warrant further exploration in preclinical and clinical studies.

Differential effect of orexin-1 and CRF-1 antagonism on stress circuits: a fMRI study in the rat with the pharmacological stressor Yohimbine.

Translational approaches to study the neural substrates of stress and assess the mechanistic efficacy of novel anti-anxiety agents necessitate the use of stressors with a similar degree of saliency across species. The alpha-2 adrenoreceptor antagonist yohimbine represents an attractive experimental tool owing to its well-documented stress-inducing properties in humans and laboratory species. We investigated the neural substrates engaged by yohimbine in the rat brain by using functional magnetic resonance imaging and mapped their modulation by neurotransmitter systems involved in stress responses. Yohimbine elicited a composite pattern of brain activation, highlighting the recruitment of cortico-striato-thalamic regions and extra-hypothalamic stress neurocircuits. This effect was strongly attenuated by the α-2-adrenoceptor agonist medetomidine and by the dopamine (DA) D1 receptor antagonist SCH23390, thus revealing a primary contribution of both norepinephrine and DA on the neurofunctional cascade elicited by the drug. Pretreatment with the corticotrophin-releasing factor type-1 receptor (CRF1R) antagonist CP154,526 produced a region-dependent inhibition of yohimbine-induced activation in the amygdala, striatum, and cingulate cortex, while the orexin type-1 receptor (OX1R) antagonists GSK1059865 robustly inhibited the response in fronto-hippocampal regions as well as in several key components of the extended amygdala. CP154,526 and GSK1059865 did not prevent yohimbine-induced plasma corticosterone release, a finding that corroborates a central origin of the effects mapped. Our findings provide novel insight into the brain substrates and neurochemical mediators engaged by the stress-inducing agent yohimbine. The differential pattern of inhibition produced by CRF1R and OX1R antagonists suggests that these two neuropeptide systems can modulate the functional response to stress via distinct central neural pathways.

Monitoring dendritic cell migration using 19F / 1H magnetic resonance imaging.

Continuous advancements in noninvasive imaging modalities such as magnetic resonance imaging (MRI) have greatly improved our ability to study physiological or pathological processes in living organisms. MRI is also proving to be a valuable tool for capturing transplanted cells in vivo. Initial cell labeling strategies for MRI made use of contrast agents that influence the MR relaxation times (T1, T2, T2*) and lead to an enhancement (T1) or depletion (T2*) of signal where labeled cells are present. T2* enhancement agents such as ultrasmall iron oxide agents (USPIO) have been employed to study cell migration and some have also been approved by the FDA for clinical application. A drawback of T2* agents is the difficulty to distinguish the signal extinction created by the labeled cells from other artifacts such as blood clots, micro bleeds or air bubbles. In this article, we describe an emerging technique for tracking cells in vivo that is based on labeling the cells with fluorine ((19)F)-rich particles. These particles are prepared by emulsifying perfluorocarbon (PFC) compounds and then used to label cells, which subsequently can be imaged by (19)F MRI. Important advantages of PFCs for cell tracking in vivo include (i) the absence of carbon-bound (19)F in vivo, which then yields background-free images and complete cell selectivityand(ii) the possibility to quantify the cell signal by (19)F MR spectroscopy.

Visualizing brain inflammation with a shingled-leg radio-frequency head probe for 19F/1H MRI.

Magnetic resonance imaging (MRI) provides the opportunity of tracking cells in vivo. Major challenges in dissecting cells from the recipient tissue and signal sensitivity constraints albeit exist. In this study, we aimed to tackle these limitations in order to study inflammation in autoimmune encephalomyelitis. We constructed a very small dual-tunable radio frequency (RF) birdcage probe tailored for (19)F (fluorine) and (1)H (proton) MR mouse neuroimaging. The novel design eliminated the need for extra electrical components on the probe structure and afforded a uniform -field as well as good SNR. We employed fluorescently-tagged (19)F nanoparticles and could study the dynamics of inflammatory cells between CNS and lymphatic system during development of encephalomyelitis, even within regions of the brain that are otherwise not easily visualized by conventional probes. (19)F/(1)H MR Neuroimaging will allow us to study the nature of immune cell infiltration during brain inflammation over an extensive period of time.

Identification of cellular infiltrates during early stages of brain inflammation with magnetic resonance microscopy.

A comprehensive view of brain inflammation during the pathogenesis of autoimmune encephalomyelitis can be achieved with the aid of high resolution non-invasive imaging techniques such as microscopic magnetic resonance imaging (µMRI). In this study we demonstrate the benefits of cryogenically-cooled RF coils to produce µMRI in vivo, with sufficient detail to reveal brain pathology in the experimental autoimmune encephalomyelitis (EAE) model. We could visualize inflammatory infiltrates in detail within various regions of the brain, already at an early phase of EAE. Importantly, this pathology could be seen clearly even without the use of contrast agents, and showed excellent correspondence with conventional histology. The cryogenically-cooled coil enabled the acquisition of high resolution images within short scan times: an important practical consideration in conducting animal experiments. The detail of the cellular infiltrates visualized by in vivo µMRI allows the opportunity to follow neuroinflammatory processes even during the early stages of disease progression. Thus µMRI will not only complement conventional histological examination but will also enable longitudinal studies on the kinetics and dynamics of immune cell infiltration.

Perfluorocarbon particle size influences magnetic resonance signal and immunological properties of dendritic cells.

The development of cellular tracking by fluorine ((19)F) magnetic resonance imaging (MRI) has introduced a number of advantages for following immune cell therapies in vivo. These include improved signal selectivity and a possibility to correlate cells labeled with fluorine-rich particles with conventional anatomic proton ((1)H) imaging. While the optimization of the cellular labeling method is clearly important, the impact of labeling on cellular dynamics should be kept in mind. We show by (19)F MR spectroscopy (MRS) that the efficiency in labeling cells of the murine immune system (dendritic cells) by perfluoro-15-crown-5-ether (PFCE) particles increases with increasing particle size (560>365>245>130 nm). Dendritic cells (DC) are professional antigen presenting cells and with respect to impact of PFCE particles on DC function, we observed that markers of maturation for these cells (CD80, CD86) were also significantly elevated following labeling with larger PFCE particles (560 nm). When labeled with these larger particles that also gave an optimal signal in MRS, DC presented whole antigen more robustly to CD8+ T cells than control cells. Our data suggest that increasing particle size is one important feature for optimizing cell labeling by PFCE particles, but may also present possible pitfalls such as alteration of the immunological status of these cells. Therefore depending on the clinical scenario in which the (19)F-labeled cellular vaccines will be applied (cancer, autoimmune disease, transplantation), it will be interesting to monitor the fate of these cells in vivo in the relevant preclinical mouse models.

GSK1614343, a novel ghrelin receptor antagonist, produces an unexpected increase of food intake and body weight in rodents and dogs.

Ghrelin is a 28-amino-acid polypeptide expressed in the stomach and hypothalamus that stimulates GH secretion, increases food intake (FI) and promotes body weight (BW) gain most likely via activation of the growth hormone secretagogue receptor type 1a (GHSR1a). GSK1614343 is a novel selective and potent GHSR antagonist with no partial agonist properties, recently characterized as GH secretion inhibitor by Sabbatini et al. [Chem Med Chem 2010;5:1450-1455]. In the present study, GSK1614343 (10 mg/kg) was not able to antagonize ghrelin-induced food consumption in rat, but unexpectedly stimulated FI and BW gain in both rats and dogs, a profile associated with decreased ghrelin plasma level. Interestingly, GSK1614343 selectively reduced the pro-opiomelanocortin mRNA levels in rat hypothalami chronically treated with the compound. To better understand the observed effects, we administered GSK1614343 (30 mg/kg) to Ghsr null mice and measured body mass components (fat, lean and free fluid) by using a NMR spectrometer. The increases of FI and BW were abolished in Ghsr null mice, while fat and lean masses increased in wild-type mice. Taken together, these results indicate that the orexigenic effect of GSK1614343 is mediated by GHSR1a and that the weight gain could be attributed to the increase of both adiposity and muscle mass, but not to fluid retention. The observed dissociation between effects on GH secretion and effects on FI/BW is inconsistent with a simple hormone-receptor model, suggesting unknown underlying regulations of the ghrelin system whose understanding require further investigation.

Neuroimaging evidence of altered fronto-cortical and striatal function after prolonged cocaine self-administration in the rat.

Cocaine addiction is often modeled in experimental paradigms where rodents learn to self-administer (SA) the drug. However, the extent to which these models replicate the functional alterations observed in clinical neuroimaging studies of cocaine addiction remains unknown. We used magnetic resonance imaging (MRI) to assess basal and evoked brain function in rats subjected to a prolonged, extended-access cocaine SA scheme. Specifically, we measured basal cerebral blood volume (bCBV), an established correlate of basal metabolism, and assessed the reactivity of the dopaminergic system by mapping the pharmacological MRI (phMRI) response evoked by the dopamine-releaser amphetamine. Cocaine-exposed subjects exhibited reduced bCBV in fronto-cortical areas, nucleus accumbens, ventral hippocampus, and thalamus. The cocaine group also showed an attenuated functional response to amphetamine in ventrostriatal areas, an effect that was significantly correlated with total cocaine intake. An inverse relationship between bCBV in the reticular thalamus and the frontal response elicited by amphetamine was found in control subjects but not in the cocaine group, suggesting that the inhibitory interplay within this attentional circuit may be compromised by the drug. Importantly, histopathological analysis did not reveal significant alterations of the microvascular bed in the brain of cocaine-exposed subjects, suggesting that the imaging findings cannot be merely ascribed to cocaine-induced vascular damage. These results document that chronic, extended-access cocaine SA in the rat produces focal fronto-cortical and striatal alterations that serve as plausible neurobiological substrate for the behavioral expression of compulsive drug intake in laboratory animals.

Statin administration before percutaneous coronary intervention: impact on periprocedural myocardial infarction.

AIMS: Peri-procedural non-Q-wave myocardial infarction is a frequent and prognostically important complication of percutaneous coronary intervention (PCI). It has been postulated that statins may reduce the rate of myocardial injury after PCI. METHODS AND RESULTS: Four hundred and fifty-one patients scheduled for elective PCI and not on statins were randomly assigned to either no treatment or to statin treatment. Statin administration was started at least 3 days before the procedure.Incidence of peri-procedural myocardial injury was assessed by analysis of creatinine kinase myocardial isoenzyme (CK-MB: upper limit of normal [ULN] 3.5 ng/ml) and cardiac troponin I (cTn I, ULN 0.10 ng/ml) before, 6 and 12 h after the intervention. A large non-Q-wave myocardial infarction was defined as a CK-MB elevation >5 times ULN alone or associated with chest pain or ST segment or T wave abnormalities. Median CK-MB peak after PCI was 1.70 (interquartile ranges 1.10-3.70) ng/ml in the Statin group and 2.20 (1.30-5.60) ng/ml in the Control group (p=0.015). Median peak of cTnI after PCI was 0.13 (0.05-0.45) ng/ml in the Statin group and 0.21 (0.06-0.85) ng/ml in the Control group (p=0.033). The incidence of a large non-Q-wave myocardial infarction was 8.0% in the Statin group and 15.6% in the Control group (p=0.012: OR=0.47; 95% CI=0.26-0.86). The incidence of cTnI elevation >5 times ULN was 23.5% in the Statin group and 32% in the Control group (p=0.043: OR=0.65; 95% CI=0.42-0.98). By logistic regression analysis, the independent predictors of CK-MB elevation >5 times ULN after PCI were intra-procedural angiographic complications (OR=9.36; 95% CI=3.06-28.64; p<0.001), statin pre-treatment (OR=0.33; 95% CI=0.13-0.86; p=0.023) and age >65 years (OR=2.58; 95% CI=1.09-6.11; p=0.031). CONCLUSIONS: Pre-procedural statin therapy reduces the incidence of large non-Q-wave myocardial infarction after PCI.

N-Acetylcysteine versus fenoldopam mesylate to prevent contrast agent-associated nephrotoxicity.

OBJECTIVES: We performed a study to assess the efficacy of fenoldopam mesylate (a specific agonist of the dopamine-1 receptor) as compared with N-acetylcysteine (NAC) in preventing contrast agent-associated nephrotoxicity (CAN). BACKGROUND: Prophylactic administration of NAC, along with hydration, prevents CAN in patients with chronic renal insufficiency who are undergoing contrast media administration. Preliminary data support the hypothesis that fenoldopam might be as effective as NAC. METHODS: One hundred ninety-two consecutive patients with chronic renal insufficiency, referred to our institution for coronary and/or peripheral procedures, were assigned randomly to receive 0.45% saline intravenously and NAC (1,200 mg orally twice daily; NAC group; n = 97) or fenoldopam (0.10 microg/kg/min; fenoldopam group; n = 95) before and after a nonionic, iso-osmolality contrast dye administration. RESULTS: Baseline creatinine levels were similar in the two groups: NAC group = 1.72 mg/dl (interquartile range, 1.55 to 1.90 mg/dl) and fenoldopam group = 1.75 mg/dl (interquartile range, 1.62 to 2.01 mg/dl) (p = 0.17). An increase of at least 0.5 mg/dl of the creatinine concentration 48 h after the procedure occurred in 4 of 97 patients (4.1%) in the NAC group and in 13 of 95 patients (13.7%) in the fenoldopam group (p = 0.019; odds ratio 0.27; 95% confidence interval 0.08 to 0.85). The amount of contrast media administration was similar in the two groups (NAC group = 160 +/- 82 ml; fenoldopam group = 168 +/- 104 ml; p = 0.54). CONCLUSIONS: N-acetylcysteine seems to be more effective than fenoldopam in preventing CAN.

Standard vs double dose of N-acetylcysteine to prevent contrast agent associated nephrotoxicity.

AIMS: Prophylactic administration of N-acetylcysteine (NAC) (600mg orally twice daily), along with hydration, prevents contrast agent-associated nephrotoxicity (CAN) induced by a low dose of non-ionic, low-osmolality contrast dye. We tested whether a double dose of NAC is more effective to prevent CAN. METHODS AND RESULTS: Two-hundred-twenty-four consecutive patients with chronic renal insufficiency (creatinine level > or =1.5mg/dl and/or creatinine clearance <60ml/min), referred to our institution for coronary and/or peripheral procedures, were randomly assigned to receive 0.45% saline intravenously and NAC at the standard dose (600mg orally twice daily; SD Group; n=110) or at a double dose (1200mg orally twice daily; DD Group; n=114) before and after a non-ionic, low-osmolality contrast dye administration. Increase of at least 0.5mg/dl of the creatinine concentration 48h after the procedure occurred in 12/109 patients (11%) in the SD Group and 4/114 patients (3.5%) in the DD Group (P=0.038; OR=0.29; 95% CI=0.09-0.94). In the subgroup with low (<140ml, or contrast ratio <=1) contrast dose, no significant difference in renal function deterioration occurred between the 2 groups. In the subgroup with high (> or =140ml, or contrast ratio >1) contrast dose, the event was significantly more frequent in the SD Group. Conclusions Double dose of NAC seems to be more effective than the standard dose in preventing CAN, especially with high volumes of non-ionic, low-osmolality contrast agent.

Intramedullary nailing of the femur with an inflatable self-locking nail: comparison with locked nailing.

We report a comparative study between an inflatable expandable nail and a traditional locked intramedullary implant in closed fractures of the femoral shaft. We matched each of 43 patients who had undergone intramedullary fixation with an inflatable expandable nail with a patient of the same sex, age (within 2 years), and fracture who had undergone statically locked intramedullary fixation with traditional nails. The mean duration of surgery was significantly shorter in the patients who were treated with the inflatable expandable nail. There were no differences in average blood loss, transfusion requirements, or hospitalization. Five of the patients who underwent traditional nailing required dynamization to achieve union. The inflatable expandable nail allows effective management of diaphyseal fractures of the femur. Interlocking is not necessary, operative times are reduced, and exposure to ionizing radiation is minimized. At present, however, the inflatable expandable nail used in the this investigation is markedly more expensive than traditional devices.

Acetylcysteine and contrast agent-associated nephrotoxicity.

OBJECTIVES: Prophylactic acetylcysteine along with hydration seems to be better than hydration alone in preventing the reduction in renal function induced by a contrast dye. BACKGROUND: Contrast media can lead to acute renal failure that may occasionally require hemodialysis. METHODS: One hundred eighty-three consecutive patients with impairment of renal function, undergoing coronary and/or peripheral angiography and/or angioplasty, were randomly assigned to receive 0.45% saline intravenously and acetylcysteine (600 mg orally twice daily; group A, n = 92) or 0.45% saline intravenously alone (group B, n = 91) before and after nonionic, low-osmolality contrast dye administration. RESULTS: The baseline serum creatinine concentrations were similar (1.5 +/- 0.4 mg/dl in group A vs. 1.5 +/- 0.4 mg/dl in group B; p = 0.37). An increase of > or =25% in the baseline creatinine level 48 h after the procedure occurred in 6 (6.5%) of 92 patients in group A and in 10 (11%) of 91 patients in group B (p = 0.22). In the subgroup with a low (<140 ml) contrast dose, renal function deterioration occurred in 5 (8.5%) of 60 patients in group B and in 0 of 60 patients in group A (p = 0.02; odds ratio [OR] 0.44, 95% confidence interval [CI] 0.35 to 0.54). In the subgroup with a high contrast dose, no difference was found (5/31 vs. 6/32 patients, p = 0.78). By multivariate analysis, the amount of contrast agent, but not the treatment strategy, was a predictor of the occurrence of contrast dye-associated nephrotoxicity (OR 2.58, 95% CI 1.1 to 4.9; p = 0.035). CONCLUSIONS: In patients with reduced renal function undergoing angiography and/or angioplasty, the amount of contrast agent, but not the administration of prophylactic acetylcysteine, was a predictor of renal function deterioration. Prophylactic acetylcysteine might provide better protection than hydration alone, only when a small volume of contrast agent is used.