Oncogenic Ras mutations are widely considered to be locked in a permanent ‘On’ state and ‘constitutively active’. Yet, many healthy people have cells possessing mutant Ras without apparent harm, and in animal models mutant Ras causes transformation only after upregulation of Ras activity. Here, we demonstrate that oncogenic K-Ras is not constitutively active but can be readily activated by upstream stimulants to lead to prolonged strong Ras activity. These data indicate that in addition to targeting K-Ras downstream effectors, interventions to reduce K-Ras activation may have important cancer-preventive value, especially in patients with oncogenic Ras mutations. As other small G proteins are regulated in a similar manner, this concept is likely to apply broadly to the entire Ras family of molecules.
There is conflicting evidence in the literature on the etiology of hypogonadism in patients with sickle cell disease (SCD). A cross-sectional study was done to determine whether hypogonadism in male patients with SCD is due to primary testicular failure or secondary pituitary/hypothalamic dysfunction and assess the association between hypogonadism and serum ferritin levels. Hormonal assessment for serum concentrations of testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) was done for 34 men with SCD and their charts were reviewed for relevant clinical variables. Eight men (24%) were classified hypogonadal based on their serum testosterone levels. These men have significantly lower LH (p = 0.001) and FSH (p = 0.01) levels than normogonadal men, indicating a central etiology. There was no significant difference between hypogonadal and normogonadal men with respect to ferritin levels (p = 0.71). Our study indicates a central etiology of hypogonadism in patients with SCD. In this small study ferritin level was not significantly related to hypogonadism.
Ferritin; Hemoglobinopathy; Hypogonadism; Testosterone
To investigate the potential diagnostic value of dual-energy CT (DECT) with virtual non-enhanced (VNE) and iodine-only images, and to determine the optimal mixed ratio of blended images for evaluation of pancreatic diseases.
Multiphasic DECT was performed in 44 patients with focal pancreatic disease. DECT was used during the pancreatic and hepatic venous phases, and a peak kilovoltage of 120 kVp was used for both non-contrast phases. For qualitative analysis of the CT images, two radiologists assessed three image sets (VNE, iodine-only and blended images) in order to determine the acceptability of VNE in replacing true non-enhanced (TNE) images, the added value of iodine-only images and the preferred blending ratio. For quantitative analyses, the CT numbers and image noise of the pancreatic parenchyma, lesions, aorta and psoas muscle were measured. The contrast-to-noise ratio of the lesion was calculated on the pancreatic phase images. The effective radiation dose for DECT and TNE images was calculated. Statistical comparisons were made using the Friedman test, the Wilcoxon test, the paired t-test and repeated measures of analysis of variation with Bonferroni correction for multiple comparisons.
The level of acceptance of the VNE images in replacing TNE images was 90.9%. Regarding the iodine-only images, 50% of the cases were found to have an added value. The linear-blended images with a weighting factor of 0.5 were preferred.
DECT was able to provide high-quality VNE images that could replace TNE images and iodine-only images showing an added value. Blended images with a weighting factor of 0.5 were preferred by the reviewers.
To determine the efficacy and safety of pelvic floor Myofascial Physical Therapy (MPT) in women with newly-symptomatic IC/PBS, as compared to Global Therapeutic Massage (GTM).
Materials and Methods
A randomized controlled trial of 10 scheduled treatments of MPT vs. GTM was performed at 11 clinical centers located in North America. We recruited women with IC/PBS with demonstrable pelvic floor tenderness on physical examination and a limitation of no more than 3 years symptom duration. The primary outcome was the proportion of responders defined as ‘moderately improved’ or ‘markedly improved’ in overall symptoms compared to baseline on a 7-point scale Global Response Assessment (GRA). Secondary outcomes included ratings for pain, urgency, frequency; the O'Leary-Sant IC Symptom and Problem Index (ICSI/ICPI) and reports of adverse events. We compared response rates between treatment arms using the exact conditional version of the Mantel-Haenszel test to control for clustering by clinical center. For secondary efficacy outcomes, cross-sectional descriptive statistics and changes from baseline were calculated.
Eighty-one women randomized to the two treatment groups had similar symptoms at baseline. The GRA response rate was 26% in the GTM group and 59% in the MPT group (p=0.0012). Pain, urgency, and frequency ratings and in ICSI/ICPI decreased in both groups during follow-up and were not significantly different between the groups. Pain was the most common adverse event, occurring at similar rates in both groups. There were no serious adverse events reported.
A significantly higher proportion of women with IC/PBS reponded to treatment with MPT than with GTM. MPT may be a beneficial therapy in women with this syndrome.
Urologic Pelvic Pain Syndrome; Interstitial Cystitis; Painful Bladder Syndrome; Physical Therapy
Pituicytoma is a rare primary tumour of the neurohypophysis or infundibulum, which masquerades as a pituitary adenoma. We present a pituicytoma case in a 45-year-old female presenting as a focal lesion of the neurohypophysis. This case report reviews the clinical, neuroimaging and histopathological features of this rare tumour in order to understand it better.
maxillofacial injury; penetrating wound
Meningitis is an important differential diagnosis in patients with fever, headache, and/or altered consciousness in the emergency department (ED). With human immunodeficiency virus (HIV) infection becoming increasingly common, patients with acquired immunodeficiency syndrome (AIDS) need to be recognised promptly to facilitate the choice of appropriate antibiotic therapy for potential opportunistic infections. Physicians should be able to recognise a patient with undiagnosed AIDS who presents to the ED and perform further confirmational tests without violating the rights of the patient. Additional tests focusing on discovering potential opportunistic pathogens should be performed. Ampicillin should be added to the empirical regimen for the coverage of Listeria meningocerebritis, which should be considered in all potentially immunocompromised hosts with suggestive clinical presentations. Failure to recognise patients with AIDS and provide antibiotics active against L monocytogenes in such hosts may lead to a catastrophic outcome.
; meningitis; myocarditis; acquired immunodeficiency syndrome; human immunodeficiency virus
Case report: An elite American football player with MPS symptoms failed to respond to standard treatments. He then received ETOIMS which completely alleviated the pain. After establishing pain control, the athlete continued with a further series of treatments to control symptoms of muscle tightness.
Conclusions: ETOIMS has a promising role in pain alleviation, increasing and maintaining range of motion, and in providing satisfactory athletic performance during long term follow up.
Dental imaging plays a significant role in the process of diagnoses of
oral cancer. In this project, an online annotation tool for dental radiology
is developed to support systematic annotation, which includes image
findings, descriptive information on the lesion, patient characteristics
and pathology data. This tool will be available for the dental
schools in US who are interested in the creation of dental image archives
for teaching and research.
The pathway of West Nile flavivirus early internalization events was mapped in detail in this study. Overexpression of dominant-negative mutants of Eps15 strongly inhibits West Nile virus (WNV) internalization, and pharmacological drugs that blocks clathrin also caused a marked reduction in virus entry but not caveola-dependent endocytosis inhibitory agent, filipin. Using immunocryoelectron microscopy, WNV particles were seen within clathrin-coated pits after 2 min postinfection. Double-labeling immunofluorescence assays and immunoelectron microscopy performed with anti-WNV envelope or capsid proteins and cellular markers (EEA1 and LAMP1) revealed the trafficking pathway of internalized virus particles from early endosomes to lysosomes and finally the uncoating of the virus particles. Disruption of host cell cytoskeleton (actin filaments and microtubules) with cytochalasin D and nocodazole showed significant reduction in virus infectivity. Actin filaments are shown to be essential during the initial penetration of the virus across the plasma membrane, whereas microtubules are involved in the trafficking of internalized virus from early endosomes to lysosomes for uncoating. Cells treated with lysosomotropic agents were largely resistant to infection, indicating that a low-pH-dependent step is required for WNV infection. In situ hybridization of DNA probes specific for viral RNA demonstrated the trafficking of uncoated viral RNA genomes to the endoplasmic reticulum.
This case presents a 34-year-old man who had a huge parasagittal meningioma. Initial treatment consisted of preoperative external carotid artery embolization and partial tumor resection. During the resection, we found that the tumor invaded the adjacent calvarium, and due to massive hemorrhage, total removal of the tumor was impossible. The patient was treated with intraoperative radiation therapy (IORT) (25 Gy via 16 MeV) as an adjunctive therapy. Eight months after IORT, we were able to remove the tumor completely without surgical difficulties. IORT can be considered an useful adjunctive therapy for the superficially located, huge, and highly vascular meningioma.
Immunized mice after inhalation of specific antigen have the following characteristic features of human asthma: airway eosinophilia, mucus and Th2 cytokine release, and hyperresponsiveness to methacholine. A model of late-phase allergic pulmonary inflammation in ovalbumin-sensitized mice was used to address the role of the alpha4 integrin (CD49d) in mediating the airway inflammation and hyperresponsiveness. Local, intrapulmonary blockade of CD49d by intranasal administration of CD49d mAb inhibited all signs of lung inflammation, IL-4 and IL-5 release, and hyperresponsiveness to methacholine. In contrast, CD49d blockade on circulating leukocytes by intraperitoneal CD49d mAb treatment only prevented the airway eosinophilia. In this asthma model, a CD49d-positive intrapulmonary leukocyte distinct from the eosinophil is the key effector cell of allergen-induced pulmonary inflammation and hyperresponsiveness.
Ten brain tumor patients underwent wide resection of the tumor followed by Intraoperative Radiation Therapy (IORT) at the first surgery or at the second salvage surgery after failure of conventional external beam irradiation. Two patients(1 meningioma, 1 glioblastoma multiforme) were treated at the first surgery and 8 patients(3 anaplastic astrocytoma, 3 glioblastoma multiforme, 1 meningioma, 1 gliosarcoma) were treated after salvage surgery. The IORT doses were ranged from 15-25 Gy depending on the tumor volume and previous radiation therapy. The neurological status(Karnofsky performance status) was improved in 4 cases, not changed in 6 cases after IORT. There were several complications after IORT; radiation necrosis, communicating hydrocephalus, wound infection, and abnormal CT findings such as diffuse low density area in an around operation site. The radiation necrosis was confirmed by operation in a recurrent meningioma patient 12 months after IORT. At follow-up, ranging from 1 to 16 months, there was no deaths. Based on our limited experiences, the IORT might be one of the adjuvant therapeutic modalities especially for the malignant brain tumors and unresectable huge meningioma.
The present study was performed to investigate the relationship between the concentrations of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI) and the CT images in 23 cases of chronic subdural hematomas (SDHs). The concentrations of t-PA and PAI-1 were quantified by enzyme-linked immunosorbent assay (ELISA). Chronic SDHs were divided into five groups according to their appearance on computed tomography: high-density (n = 4), isodensity (n = 8), low-density (n = 5), mixed-density (n = 3), layering (n = 3) types. The volume of hematoma was measured with an image analyzing software program. The concentrations of t-PA were higher in layering (41.2 +/- 0.3 ng/ml, mean +/- standard error of the mean) and high-density (40.0 +/- 1.1 ng/ml) types compared to those of low-density (23.3 +/- 4.1 ng/ml) and iso-density (25.1 +/- 3.7 ng/ml) types. The concentrations of PAI-1 were lower in layering (95.9 +/- 1.0 ng/ml) and high-density (103.4 +/- 34.5 ng/ml) types compared to that of low-density (192.5 +/- 2.6 ng/ml) type. So the ratio between t-PA and PAI-1 (t-PA/PAI) was greater in layering and high-density types. The volume of hematoma was larger in mixed-density and layering types but statistically insignificant. These results presumably suggest that the ratio between t-PA and PAI concentration may contribute to the pathogenesis of the chronic SDH.
BACKGROUND: N-Formyl-methionyl-leucyl-phenylalanine (FMLP) is a bacterial oligopeptide which stimulates neutrophil chemotaxis, degranulation and superoxide generation. Inhalation of FMLP produces bronchoconstriction in man; in the rabbit this is in part neutrophil dependent. The effects of inhalation of FMLP on peripheral blood leucocytes in normal subjects has been studied. METHODS: This was an open study in non-asthmatic subjects. Change in total peripheral white cell count were studied for 15 minutes after inhalation of 0.4 mumol FMLP in six subjects. Change in total and differential white cell count and spontaneous neutrophil chemiluminescence were then studied five and 30 minutes after inhalation of 0.4 mumol FMLP (n = 7) or diluent (n = 4). Finally, leucocytes from three subjects were labelled ex vivo with technetium-99m labelled sulphur colloid and reinfused. The effect of inhalation of FMLP or diluent on pulmonary neutrophil flux was studied by continuous gamma scanning of a pulmonary window. RESULTS: Leucopenia occurs rapidly after inhalation of FMLP, the nadir of the white cell count (53% of baseline) occurring at four minutes. This was followed by a rebound increase in white cell count evident at 15 minutes (154% of baseline). Five minutes after inhalation of 0.4 mumol FMLP, neutropenia (17% of baseline) and monocytopenia (40% of baseline) were seen followed again by a neutrophilia (213% of baseline at 30 minutes). The eosinophil count was significantly reduced at 30 minutes (24% of baseline). Neutrophil chemiluminescence was elevated (186% of baseline) at the time of the neutropenia. There was no influx of labelled cells to the lung during the period of neutropenia. CONCLUSION: FMLP inhalation activates circulating leucocytes. In vivo production of FMLP in the airway could contribute to bronchial inflammation during bacterial infection.
Autoantibodies to a polymerase III transcription factor, La (SS-B), are frequently detected in the serum of patients with Sjogren's syndrome and systemic lupus erythematosus. To define the humoral immune response to this protein, we analyzed the patterns of antibody recognition toward 13 recombinant La peptides by immunoblotting and determined the heterogeneity of antibodies reactive with the immunodominant epitopes. The smallest epitopes that were strongly antigenic and recognized by greater than 70% of sera tested (immunodominant) were encoded by the subclones BgX and XA located in the 5' and 3' halves of the La cDNA, respectively. Conformation of the immunodominant La peptides played a major role in antibody recognition. Although greater diversity in antibody binding to carboxyl-terminal La peptides was observed, the overall pattern of peptide recognition by anti-La antibodies was similar in different diseases. The antibody responses to the immunodominant peptides were strongly correlated (r = 0.68, P less than 0.001). One- and two-dimensional isoelectric focusing of affinity purified IgG anti-La peptide antibodies revealed restricted heterogeneity and oligoclonal bands (kappa light chains). These observations suggest that anti-La antibodies are induced and/or maintained by the self antigen and that their diversity is constrained either by mechanisms related to tolerance or by affinity maturation of the humoral immune response.