CD38 Knockout Mice Show Significant Protection Against Ischemic Brain Damage Despite High Level Poly-ADP-Ribosylation.

Several enzymes in cellular bioenergetics metabolism require NAD+ as an essential cofactor for their activity. NAD+ depletion following ischemic insult can result in cell death and has been associated with over-activation of poly-ADP-ribose polymerase PARP1 as well as an increase in NAD+ consuming enzyme CD38. CD38 is an NAD+ glycohydrolase that plays an important role in inflammatory responses. To determine the contribution of CD38 activity to the mechanisms of post-ischemic brain damage we subjected CD38 knockout (CD38KO) mice and wild-type (WT) mice to transient forebrain ischemia. The CD38KO mice showed a significant amelioration in both histological and neurologic outcome following ischemic insult. Decrease of hippocampal NAD+ levels detected during reperfusion in WT mice was only transient in CD38KO animals, suggesting that CD38 contributes to post-ischemic NAD+ catabolism. Surprisingly, pre-ischemic poly-ADP-ribose (PAR) levels were dramatically higher in CD38KO animals compared to WT animals and exhibited reduction post-ischemia in contrast to the increased levels in WT animals. The high PAR levels in CD38 mice were due to reduced expression levels of poly-ADP-ribose glycohydrolase (PARG). Thus, the absence of CD38 activity can not only directly affect inflammatory response, but also result in unpredicted alterations in the expression levels of enzymes participating in NAD+ metabolism. Although the CD38KO mice showed significant protection against ischemic brain injury, the changes in enzyme activity related to NAD+ metabolism makes the determination of the role of CD38 in mechanisms of ischemic brain damage more complex.

Nicotinamide mononucleotide inhibits post-ischemic NAD(+) degradation and dramatically ameliorates brain damage following global cerebral ischemia.

Nicotinamide adenine dinucleotide (NAD(+)) is an essential cofactor for multiple cellular metabolic reactions and has a central role in energy production. Brain ischemia depletes NAD(+) pools leading to bioenergetics failure and cell death. Nicotinamide mononucleotide (NMN) is utilized by the NAD(+) salvage pathway enzyme, nicotinamide adenylyltransferase (Nmnat) to generate NAD(+). Therefore, we examined whether NMN could protect against ischemic brain damage. Mice were subjected to transient forebrain ischemia and treated with NMN or vehicle at the start of reperfusion or 30min after the ischemic insult. At 2, 4, and 24h of recovery, the proteins poly-ADP-ribosylation (PAR), hippocampal NAD(+) levels, and expression levels of NAD(+) salvage pathway enzymes were determined. Furthermore, animal's neurologic outcome and hippocampal CA1 neuronal death was assessed after six days of reperfusion. NMN (62.5mg/kg) dramatically ameliorated the hippocampal CA1 injury and significantly improved the neurological outcome. Additionally, the post-ischemic NMN treatment prevented the increase in PAR formation and NAD(+) catabolism. Since the NMN administration did not affect animal's temperature, blood gases or regional cerebral blood flow during recovery, the protective effect was not a result of altered reperfusion conditions. These data suggest that administration of NMN at a proper dosage has a strong protective effect against ischemic brain injury.

Control of epigenetic states by WT1 via regulation of de novo DNA methyltransferase 3A.

Although tumour suppressor gene hypermethylation is a universal feature of cancer cells, little is known about the necessary molecular triggers. Here, we show that Wilms' tumour 1 (WT1), a developmental master regulator that can also act as a tumour suppressor or oncoprotein, transcriptionally regulates the de novo DNA methyltransferase 3A (DNMT3A) and that cellular WT1 levels can influence DNA methylation of gene promoters genome-wide. Specifically, we demonstrate that depletion of WT1 by short-interfering RNAs leads to reduced DNMT3A in Wilms' tumour cells and human embryonal kidney-derived cell lines. Chromatin immunoprecipitation assays demonstrate WT1 recruitment to the DNMT3A promoter region and reporter assays confirm that WT1 directly transactivates DNMT3A expression. Consistent with this regulatory role, immunohistochemical analysis shows co-expression of WT1 and DNMT3A proteins in nuclei of blastemal cells in human fetal kidney and Wilms' tumours. Using genome-wide promoter methylation arrays, we show that human embryonal kidney cells over-expressing WT1 acquire DNA methylation changes at specific gene promoters where DNMT3A recruitment is increased, with hypermethylation being associated with silencing of gene expression. Elevated DNMT3A is also demonstrated at hypermethylated genes in Wilms' tumour cells, including a region of long-range epigenetic silencing. Finally, we show that depletion of WT1 in Wilms' tumour cells can lead to reactivation of gene expression from methylated promoters, such as TGFB2, a key modulator of epithelial-mesenchymal transitions. Collectively, our work defines a new regulatory modality for WT1 involving elicitation of epigenetic alterations which is most likely crucial to its functions in development and disease.

Mitochondrial dynamics: cell-type and hippocampal region specific changes following global cerebral ischemia.

Mitochondria are organelles that undergo continuous cycles of fission and fusion. This dynamic nature of mitochondria is important for cell physiology. Transgenic mouse models that express mitochondria targeted fluorescence protein, in either neurons or astrocytes, were used to examine the role of alterations in mitochondrial morphology in mechanisms of ischemic brain injury. The animals were subjected to global cerebral ischemia and allowed to recover before their brains were perfusion fixed and processed for histology and confocal microscopy. After capturing z-stack images from different hippocampal sub-regions, mitochondrial organelles were 3D reconstructed using volocity software and then their morphological parameters were calculated. The data shows cell-type specific alterations in mitochondrial dynamics following ischemia. Fission is activated in all hippocampal areas at 2 h recovery with mitochondria in CA1 becoming progressively more fragmented during the 24 h recovery period. Mitochondria in CA3 and dentate gyrus neurons started to re-fuse after 24 h of recirculation; this was even more pronounced 3 days after ischemia. Astrocytic mitochondria underwent transient fission 2 h after ischemic insult and regained their normal shape at 24 h recovery. Surprisingly, no positive correlation was found between increased nitrotyrosine levels and mitochondrial fission, particularly in ischemia resistant CA3 and dentate gyrus neurons. Our data suggest that ischemia resistant neurons are able to shift their mitochondrial dynamics toward fusion after extensive fragmentation. The re-fusion ability of fragmented mitochondria is most likely a vital feature for cell survival.

Mitochondrial oxygen consumption deficits in skeletal muscle isolated from an Alzheimer's disease-relevant murine model.

BACKGROUND: Age is considered a primary risk factor for neurodegenerative diseases including Alzheimer's disease (AD). It is also now well understood that mitochondrial function declines with age. Mitochondrial deficits have been previously assessed in brain from both human autopsy tissue and disease-relevant transgenic mice. Recently it has been recognized that abnormalities of muscle may be an intrinsic aspect of AD and might contribute to the pathophysiology. However, deficits in mitochondrial function have yet to be clearly assessed in tissues outside the central nervous system (CNS). In the present study, we utilized a well-characterized AD-relevant transgenic mouse strain to assess mitochondrial respiratory deficits in both brain and muscle. In addition to mitochondrial function, we assessed levels of transgene-derived amyloid precursor protein (APP) in homogenates isolated from brain and muscle of these AD-relevant animals. RESULTS: We now demonstrate that skeletal muscles isolated from these animals have differential levels of mutant full-length APP depending on muscle type. Additionally, isolated muscle fibers from young transgenic mice (3 months) have significantly decreased maximal mitochondrial oxygen consumption capacity compared to non-transgenic, age-matched mice, with similar deficits to those previously described in brain. CONCLUSIONS: This is the first study to directly examine mitochondrial function in skeletal muscle from an AD-relevant transgenic murine model. As with brain, these deficits in muscle are an early event, occurring prior to appearance of amyloid plaques.

Attitudinal concordance toward uptake and disclosure of genetic testing for cancer susceptibility in patient-family member dyads.

Decisions for cancer susceptibility genetic testing (CSGT) uptake and dissemination of results occur within the family context. A national survey was performed with 990 patient-family member dyads (participation rate:76.2%), with paired questionnaires examining attitudes toward CSGT uptake and disclosure of results in response to a hypothetical scenario in which a reliable CSGT was available for the specific cancer a patient was being treated. While most patients and family members responded they would uptake or recommend CSGT if available, concordance between the dyads was poor for both patient's testing (agreement rate 77.5%, weighted κ=0.09) and first-degree relatives' testing(agreement rate 78.0%, weighted κ=0.09). Most patients (93.2%) and family members (92.9%) indicated that patients should disclose positive CSGT results to family members, with dyadic agreement of 89.1% (κ=0.15). However, there were substantial disagreement regarding when disclosure should take place, who should make the disclosure (the patient or the health care professionals), and to whom the results should be disclosed. Patients and family members may hold different attitudes toward CSGT uptake of and disclosure of results within the family. Our findings reinforce the need for a family system approach to incorporate perspectives of patients as well as their family members.

Predictors of a Favorable Response to Erector Spinae Plane Block for Lumbosacral Radiculopathy.

BACKGROUND: The erector spinae plane block (ESPB), which was introduced to manage the thoracic pain, is a technical easy and less invasive ultrasound-guided technique. Although the ESPB is used widely in various clinical situations, no studies have evaluated the association between the clinical outcomes of the ESPB and the numerical changes of the perfusion index (PI). OBJECTIVES: The purpose of this study is to investigate the association between the clinical response following ESPB and other possible factors including the changes of PI. STUDY DESIGN: Prospective, nonrandomized, and an open-label study. SETTING: The pain clinic of a tertiary university hospital. METHODS: This study included 91 patients of low back pain with degenerative spinal disease who received L4 ESPB using 20 mL of 0.2% ropivacaine. For the predication of clinical outcome, the PI was measured for 30 min at the blocked side subsequent to the ESPB. Various demographic data were also analyzed to predict the clinical outcomes. RESULTS: The PI of the responder group was higher value than that of the nonresponder group until 30 min but did not show any statistically significant differences. Multivariate logistic regression analysis revealed that the duration of pain (odds ratio [OR], 0.95; 95% CI, 0.90-1.00; P = 0.043), the right side injection (OR, 3.87; 95% CI, 1.42-10.55; P = 0.008), and the PI ratio of 1.5-3 at 10 min (OR, 3.79; 95% CI, 1.36-10.57; P = 0.011), were independent factors associated with successful outcomes. LIMITATION: The responder and the nonresponders were categorized using only changes of the numeric rating scale. The categorization based on the changes of functional disability or quality of life was not used. CONCLUSION: The right side injection, duration of pain less than 3 months, PI ratio of 1.5-3 at 10 min following the ESPB were associated with successful clinical outcomes.

Predictors of a Successful Outcome Following a Thoracic Erector Spinae Plane Block for Cervical Radiculopathy.

BACKGROUND: The erector spinae plane block (ESPB) is an interfascial plane block for managing neuropathic thoracic pain. Although the ESPB is applied widely in various clinical situations, no studies have evaluated the association between the analgesic outcomes of the ESPB and the numerical changes in the perfusion index (PI) and PI ratio. OBJECTIVES: The purpose of this study is to investigate the association between the clinical response following ESPB and other possible factors, including changes in the PI and PI ratio. STUDY DESIGN: A prospective, nonrandomized, and open-label study. SETTING: The pain clinic of a tertiary university hospital. METHODS: This study included 92 patients with neck or arm pain who received T2 ESPB using 20 mL of 0.2% ropivacaine. To aid in the prediction of clinical outcomes, the PI was measured at the blocked side for 30 minutes as soon as the ESPB was finished. Various demographic data were also analyzed to predict the clinical outcomes. RESULTS: Among 92 patients, 59 patients (64%) showed successful treatment outcomes (> 50% reduction in the numerical rating scale score or > 30% reduction in the neck disability index). The baseline PI of the responders was statistically higher than the nonresponders' (P < 0.05). Also, the responders' PI demonstrated statistically higher values than the nonresponders' at the time points of 4, 6, and 8 minutes after the ESPB. Multivariate logistic regression analysis revealed that a higher baseline PI (OR, 1.91; 95% CI, 1.27-2.86; P = 0.002) was an independent factor associated with a successful outcome. LIMITATIONS: Only a small number of patients with nonspinal diseases were included, except for those who had cervical radiculopathy. Therefore, it is hard to conclude that thoracic ESPB has any therapeutic benefits to patients with nonspinal diseases such as complex regional pain syndrome, adhesive capsulitis, or post-thoracotomy pain syndrome. CONCLUSION: A successful outcome at 4 weeks after T2 ESPB was achieved in 64% of patients with cervical radiculopathy. A higher baseline PI value was an independent factor associated with a successful response to T2 ESPB.

Sympatholytic Effect of the High Thoracic Erector Spinae Plane Block.

BACKGROUND: The erector spinae plane block (ESPB), which was introduced for the management of thoracic pain, is a technically easy and relatively noninvasive ultrasound (ULSD)-guided technique. Although the ESPB is used widely in variable clinical situations, its sympatholytic effect has never been studied. OBJECTIVES: The purpose of this study is to demonstrate the sympatholytic effect of the high thoracic ESPB by comparing the blocked and unblocked sides of patients' upper extremities, using the changes in the perfusion index (PI). STUDY DESIGN: Prospective, single-group, and open-label study. SETTING: The study was carried out in the pain clinic of a tertiary university hospital. METHODS: This study included 47 patients with upper extremity pain and various diseases who received T2 or T3 ESPBs using 20 mL of 0.2% ropivacaine. For the evaluation of the sympatholytic effect, measurements were taken on the numeric rating scale (NRS), the neck disability index (NDI), and the PI. RESULTS: The PIs of the blocked sides demonstrated significant increases at 10, 20, and 30 minutes compared to the PIs of the baseline and unblocked sides (P < 0.001). The PI ratio at 10 minutes was 2.74 ± 1.65, which was the highest value during the measurement period. Until 30 minutes after the ESPB, the PI ratio was significantly higher in the blocked side than in the unblocked side. During the study period, significant reductions in NRS and NDI scores were found irrespective of disease entity. LIMITATION: The period of PI measurement was only 30 minutes, so we could not determine the time point when the PI returned to the baseline value. CONCLUSION: The high thoracic ESPB was effective in relieving upper extremity pain in diverse disease entities, and the PIs of patients' blocked sides demonstrated significant increases over the baseline value and contralateral unblocked sides.

Congenital diaphragmatic hernia interval on chromosome 8p23.1 characterized by genetics and protein interaction networks.

Chromosome 8p23.1 is a common hotspot associated with major congenital malformations, including congenital diaphragmatic hernia (CDH) and cardiac defects. We present findings from high-resolution arrays in patients who carry a loss (n = 18) or a gain (n = 1) of sub-band 8p23.1. We confirm a region involved in both diaphragmatic and heart malformations. Results from a novel CNVConnect algorithm, prioritizing protein-protein interactions between products of genes in the 8p23.1 hotspot and products of previously known CDH causing genes, implicated GATA4, NEIL2, and SOX7 in diaphragmatic defects. Sequence analysis of these genes in 226 chromosomally normal CDH patients, as well as in a small number of deletion 8p23.1 patients, showed rare unreported variants in the coding region; these may be contributing to the diaphragmatic phenotype. We also demonstrated that two of these three genes were expressed in the E11.5-12.5 primordial mouse diaphragm, the developmental stage at which CDH is thought to occur. This combination of bioinformatics and expression studies can be applied to other chromosomal hotspots, as well as private microdeletions or microduplications, to identify causative genes and their interaction networks.

Application of simplified Fuhrman grading system in clear-cell renal cell carcinoma.

OBJECTIVE: To investigate the efficacy of simplified (two- or three-tiered) Fuhrman grading systems as prognostic indicators in clear-cell renal cell carcinoma (RCC). PATIENTS AND METHODS: By reviewing records, various clinicopathological factors were assessed in 431 patients who received surgical management for clear-cell RCC. A conventional four-tiered Fuhrman grading system was compared with a modified two-tiered grading system (Fuhrman grades I and II were combined as one class, and grades III and IV as another) and also with a three-tiered grading system (only grades I and II were combined). Efficacies of grading systems were assessed via univariate analyses and multivariate models for prediction of cancer-specific survival. RESULTS: In univariate analysis, the four-tiered and three-tiered grading systems showed similar accuracies (76.5 vs 76.2%, P =0.614) for predicting cancer-specific survival, which were greater than that of the two-tiered system (72.5%; both P < 0.05). Of the three grading systems, only the three-tiered system was an independent predictor of cancer-specific survival in multivariate analysis (P = 0.046). When receiver operating characteristic-derived areas under the curve (AUCs) of multivariate models for predicting cancer-specific survivals were assessed, AUCs for models including the three-tiered Fuhrman grading system and the conventional four-tiered Fuhrman grading system were the same (95.3%), followed by that of a model incorporating the two-tiered grading system (95.1%). CONCLUSION: A modified, three-tiered Fuhrman grading system can be considered an appropriate option in the application of a nuclear grading system to the prognostication of clear-cell RCC in both univariate analysis and multivariate model setting.

Mutations of Helicobacter pylori associated with fluoroquinolone resistance in Korea.

BACKGROUND AND AIM: Fluoroquinolone resistance of Helicobacter pylori is known to be dependent on mutations in the QRDR of gyrA. This study was performed to investigate the distribution of gyrA point mutations and to evaluate the impact of the mutations on second-line H. pylori eradication therapy. METHODS: After H. pylori isolation from gastric mucosal specimens, fluoroquinolone resistance was examined using the agar dilution method. DNA sequencing of the QRDR of gyrA was performed in 89 fluoroquinolone-resistant and 27 fluoroquinolone-susceptible isolates. Transformation experiments were performed to confirm mutations in the resistant strains. The eradication rates of moxifloxacin-containing triple therapy were evaluated depending on the resistance of fluoroquinolone. RESULTS: The gyrA mutations were detected in 75.3% (55 of 73 strains) of the primary resistant strains and 100% (16 strains) of the secondary resistant strains. The most common mutations were Asp-91 (36.0%) and Asn-87 (33.7%). The MIC values in the transformed strains differed depending on the gyrA mutations, N87, and D91. Six patients with fluoroquinolone-resistant strains received moxifloxacin-containing triple therapy as the second-line therapy, and two of three patients with Asn-87 mutations (66.7%) failed in the eradication. By contrast, three patients with Asp-91 mutations had successful eradication treatment. CONCLUSIONS: Fluoroquinolone resistance of H. pylori was caused by gyrA Asn-87 and Asp-91 point mutations. The Asn-87 mutation seems to be an important determinant of failure of fluoroquinolone-containing triple eradication therapy based on eradication results.

The analgesic potency dose of remifentanil to minimize stress response induced by intubation and measurement uncertainty of Surgical Pleth Index.

BACKGROUND: The aim of this study was to evaluate the analgesic potency dose of remifentanil to maintain Surgical Pleth Index (SPI) values at less than 50 after intubation in patients undergoing general anesthesia with target-controlled infusion of propofol and remifentanil. METHODS: We randomly allocated 120 patients to receive one of three remifentanil target effect-site concentrations (5, 7, or 9 ng×mL-1) during intubation. The target effect-site concentrations of propofol were adjusted within a range of 2.5-3 µg×mL-1 to maintain bispectral index values at less than 60 during anesthesia induction. A reusable SPI sensor was placed on the index finger of the arm, and the SPI values were continuously recorded. The predicted probability for maintaining the SPI values at less than 50 after intubation against the cumulative amount of remifentanil was analyzed using logistic regression. The measurands were the baseline SPI value in patients without pain scheduled for surgery, and the maximal SPI value after intubation in patients receiving remifentanil with a target effect-site concentration of 7 ng×mL-1. RESULTS: The estimated cumulative amount of remifentanil associated with a 50% and 95% probability of maintaining the SPI values at less than 50 after intubation were 135.0 µg and 330.4 µg, respectively. The estimated expanded uncertainty for the baseline and maximal SPI values after intubation in patients scheduled for surgery were 54.9±44.4 and 54.1±37.9, respectively, which corresponded to a confidence level of approximately 95%. CONCLUSIONS: The analgesic potency dose of remifentanil to maintain SPI values at less than 50 after intubation was 135.0 µg.

Comparison between the robo-horse and real horse movements for hippotherapy.

While the novel robotic hippotherapy system has gradually gained clinical application for therapeutic intervention on postural and locomotor control in individuals with neurological or musculoskeletal impairments, the system's validity and reliability for the robotic hippotherapy system has not been well established. The objective of the current study was to investigate the validity and test-retest reliability of the robotic hippotherapy system by comparing with real horse movements. The 3-axis accelerometer sensors attached on the robotic and real horse saddles were used to collect 3-dimensional acceleration data at a preferred walking velocity. Linear regression analysis showed an excellent correlation in the time-to-peak acceleration (TPA) (R(2)=0.997), but little correlation in X-axis acceleration between the real and robotic horses (R(2)=0.177), thus confirming consistent time control and a certain degree of variability between the robotic and real horse movements. The mean resultant accelerations for a real horse and robotic horse were 3.22 m/s(2) and 0.67 m/s(2), respectively, accounting for almost five times greater acceleration in the real horse than the robotic horse.

Utilizing commercial microwave for rapid and effective immunostaining.

There is an accumulating literature demonstrating the application of microwaves across a wide spectrum of histological techniques. Although exposure to microwaves for short periods resulted in substantial acceleration of all procedures this technique still is not adopted widely. In part, this may be due to concerns over solutions that will avoid induction of thermal damage to the tissue when using standard microwave. Here, we offer a cooling setup that can be used with conventional microwave ovens. We utilized dry ice for effective cooling during microwave irradiation of tissue samples. To prevent overheating, the cups with tissue during exposure to microwaves were surrounded with powdered dry ice. Since the dry ice does not touch the walls of the cups, freezing is prevented. Overheating is avoided by alternating the microwave treatment with 1-2 min time periods when the cups are cooled outside of the microwave oven. This technique was used on mouse brain sections that were immunostained with microglia-specific CD68 antiserum and astrocyte labeling GFAP antibody. Both standard and microwave-assisted immonolabeling gave comparable results visualizing cells with fine processes and low background signal. Short incubation time in the microwave requires high concentrations of antibody for tissue immunostaining. We show that by prolonging the microwaving procedure we were able to reduce the antibody concentration to the levels used in standard immunostaining protocol. In summary, our technique gives a possibility to use a conventional microwave for rapid and effective immunolabeling resulting in reduced amount of antibody required for satisfactory immunostaining.

Mitochondrial dysfunction and NAD(+) metabolism alterations in the pathophysiology of acute brain injury.

Mitochondrial dysfunction is commonly believed to be one of the major players in mechanisms of brain injury. For several decades, pathologic mitochondrial calcium overload and associated opening of the mitochondrial permeability transition (MPT) pore were considered a detrimental factor causing mitochondrial damage and bioenergetics failure. Mitochondrial and cellular bioenergetic metabolism depends on the enzymatic reactions that require NAD(+) or its reduced form NADH as cofactors. Recently, it was shown that NAD(+) also has an important function as a substrate for several NAD(+) glycohydrolases whose overactivation can contribute to cell death mechanisms. Furthermore, downstream metabolites of NAD(+) catabolism can also adversely affect cell viability. In contrast to the negative effects of NAD(+)-catabolizing enzymes, enzymes that constitute the NAD(+) biosynthesis pathway possess neuroprotective properties. In the first part of this review, we discuss the role of MPT in acute brain injury and its role in mitochondrial NAD(+) metabolism. Next, we focus on individual NAD(+) glycohydrolases, both cytosolic and mitochondrial, and their role in NAD(+) catabolism and brain damage. Finally, we discuss the potential effects of downstream products of NAD(+) degradation and associated enzymes as well as the role of NAD(+) resynthesis enzymes as potential therapeutic targets.

Surgical treatment improves clinical and functional outcomes for patients who sustain incomplete bisphosphonate-related femur fractures.

OBJECTIVE: To describe the outcomes for patients treated at a single institution, who sustained incomplete bisphosphonate-induced femoral fractures. DESIGN: Retrospective review. SETTING: University-based academic medical center. PATIENTS: Thirty-one patients with 43 incomplete fractures met the inclusion criteria. INTERVENTION: Nonoperative management or surgical intervention for fractures with refractory symptoms or progression of fracture lucency on radiographs. MAIN OUTCOME MEASUREMENTS: Radiographic assessments and the Short Musculoskeletal Functional Assessment to gauge functional status. RESULTS: The cohort was all women with an average age of 69.2 (range: 46-92) years and had been treated with bisphosphonate therapy for an average of 9.1 (range: 5-20) years. The average healing time for all incomplete fractures was 9.4 (range: 1.5-36) months. Forty-nine percent of the fractures (21 of 43 fractures) were ultimately treated with surgery for impending complete fracture or failure of nonsurgical management. Of the incomplete fractures treated with surgery, 81% became pain free and 100% were radiographically healed at a mean of 7.1 (range: 1.5-12) months. In contrast, of the nonoperatively treated incomplete fractures, only 64% were pain free at latest follow-up, with only 18% of fractures demonstrating radiographic evidence of healing at an average of 11 (range: 6-24) months. Standardized dysfunction index from the Short Musculoskeletal Functional Assessment was better (19.7) in the surgical group than in the nonsurgical group (19.7 vs. 25.7, P = 0.0017). CONCLUSIONS: A higher percentage of patients treated surgically became asymptomatic and demonstrated radiographic evidence of healing earlier than those treated nonsurgically. Surgical intervention is effective for relief of symptoms when treating incomplete bisphosphonate-related femur fractures, and patients should be counseled to the potential benefits of prophylactic surgery. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Fatty diets retarded the propulsive function of and attenuated motility in the gastrointestinal tract of rats.

Digestive functions are considered to be alterable by the ingestion of fatty diets. This study aimed to investigate the hypothesis that dietary fats may exert site-specific effects on the propulsive functions of the gastrointestinal (GI) tract. After male Wistar rats were fed either low-fat diet or high-fat diet (HFD) for 8 weeks, the propulsive function of the luminal contents of the entire GI tract was simultaneously examined in vivo. In comparison with a low-fat diet, an HFD significantly increased the body weight gains but significantly decreased the diet and caloric intakes, fecal weights, and fecal pellet numbers. Gastric emptying in the HFD-fed rats tended to be delayed, but this was not significant. High-fat diet feeding significantly slowed the small bowel transit times, and the luminal residuals emptied from the gastric antrum were largely accumulated in the proximal parts of the small intestine. An HFD also significantly prolonged the colonic transit times. In conclusion, fatty diets retarded the propulsive function of the entire GI tract, and the delayed gastroduodenal transit of fatty diets may act as a primary causal factor for producing the attenuated motile function of the GI tract in rats.