Investigating the potential anti-depressive mechanisms of statins: a transcriptomic and Mendelian randomization analysis.

Observational studies and randomized controlled trials presented inconsistent findings on the effects of cholesterol-lowering statins on depression. It therefore remains unclear whether statins have any beneficial effects on depression, and if so, what the underlying molecular mechanisms are. Here, we aimed to use genomic approaches to investigate this further. Using Connectivity Map (CMap), we first investigated whether statins and antidepressants shared pharmacological effects by interrogating gene expression responses to drug exposure in human cell lines. Second, using Mendelian randomization analysis, we investigated both on-target (through HMGCR inhibition) and potential off-target (through ITGAL and HDAC2 inhibition) causal effects of statins on depression risk and depressive symptoms, and traits related to the shared biological pathways identified from CMap analysis. Compounds inducing highly similar gene expression responses to statins in HA1E cells (indicated by an average connectivity score with statins > 90) were found to be enriched for antidepressants (12 out of 38 antidepressants; p = 9E-08). Genes perturbed in the same direction by both statins and antidepressants were significantly enriched for diverse cellular and metabolic pathways, and various immune activation, development and response processes. MR analysis did not identify any significant associations between statin exposure and depression risk or symptoms after multiple testing correction. However, genetically proxied HMGCR inhibition was strongly associated with alterations in platelets (a prominent serotonin reservoir) and monocyte percentage, which have previously been implicated in depression. Genetically proxied ITGAL inhibition was strongly associated with basophil, monocyte and neutrophil counts. We identified biological pathways that are commonly perturbed by both statins and antidepressants, and haematological biomarkers genetically associated with statin targets. Our findings warrant pre-clinical investigation of the causal role of these shared pathways in depression and potential as therapeutic targets, and investigation of whether blood biomarkers may be important considerations in clinical trials investigating effects of statins on depression.

Nasopharyngeal carcinoma: relationship between invasion of the prevertebral space and distant metastases.

PURPOSE: To identify primary sites of nasopharyngeal carcinoma (NPC) invasion on the staging head and neck magnetic resonance imaging (MRI) that correlate with distant metastases (DM). MATERIALS AND METHODS: Staging head and neck MRI examinations of 579 NPC patients were assessed for primary tumour invasion into 16 individual sites, primary stage (T) and nodal stage (N). Results were correlated with distant metastasis-free survival (DMFS) using the Cox regression, and the diagnostic performance of significant independent markers for DM was calculated. In addition, sites of primary tumour invasion were correlated also with involvement of the first echelon of ipsilateral nodes (FEN+) using logistic regression. RESULTS: Distant metastases were present in 128/579 NPC patients (22.1%) after intensity-modulated radiotherapy (IMRT)/chemo-IMRT and 5-year DMFS was 78.8%. Prevertebral space invasion (PVS+) and N stage, but not T stage, were independent prognostic markers of DMFS (p = 0.016, < 0.001, and 0.433, respectively). Compared to stage N3, PVS invasion had a higher sensitivity (28.1 vs. 68.8%), but lower specificity (90.5 vs. 47.4%) and accuracy (76.7 vs. 48.9%) for correlating patients with DM. PVS invasion, together with parapharyngeal fat space invasion (PPFS+), was also an independent predictive marker of FEN+. CONCLUSION: PVS was the only site of primary tumour invasion that independently correlated with DM, and together with PPFS + was an independent prognostic marker of FEN+, but the low specificity and accuracy of PVS invasion limits its use as a prognostic marker of DM.

Pretreatment and early intratreatment prediction of clinicopathologic response of head and neck cancer to chemoradiotherapy using 1H-MRS.

PURPOSE: To determine if choline (cho) identified by proton magnetic resonance spectroscopy ((1)H-MRS) performed pretreatment and early in the course of treatment predicts clinicopathologic response of head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: In all, 60 patients with HNSCC scheduled to undergo concurrent chemoradiotherapy or radiotherapy alone were recruited. (1)H-MRS was performed pretreatment and early intratreatment (2 weeks after start of treatment). Cho:creatine and cho:water ratios at each timepoint and change in the ratios between the two timepoints were correlated with locoregional failure, distant metastases, overall survival, and cancer-related death. Statistical analysis was performed using logistic regression and chi-square and a P-value of < 0.05 was considered statistically significant. RESULTS: Cho was identified in 47/49 successful pretreatment spectra and 42 of these 47 underwent successful (1)H-MRS early intratreatment, of which 21 showed persistent cho. Locoregional failure occurred in 15, distant metastases in 6, and death in 15 patients; the follow-up period in survivors ranged from 13-64 months (mean, 39 months). No statistically significant correlation was found between (1)H-MRS parameters and clinical endpoints. CONCLUSION: The pretreatment cho and change in cho early during a course of treatment did not predict clinical outcome.

Monitoring of treatment response after chemoradiotherapy for head and neck cancer using in vivo 1H MR spectroscopy.

Elevated choline (Cho) level has been documented on proton magnetic resonance spectroscopy ((1)H MRS) in head and neck squamous cell carcinoma and therefore percentage changes in Cho levels after chemoradiotherapy may serve as a marker of residual cancer in a post-treatment mass (PTM). Forty-six patients underwent (1)H MRS before treatment and the 30 patients with a PTM underwent repeat (1)H MRS at 6 weeks post-treatment. The percentage change in Cho/creatine and Cho/water ratios were correlated with residual cancer. The mean pretreatment Cho/creatine and Cho/water ratios were 2.24 and 1.20 x 10(-3), respectively. Cho persisted in four out of nine PTMs with residual cancer. Cho was absent in five out of nine PTMs with residual cancer and 21/21 PTMs without cancer. The number of PTMs with persistent Cho was too small to allow analysis of percentage change in ratios but the presence of Cho in a PTM showed significant correlation with residual cancer (p = 0.0046), producing a sensitivity, specificity, positive predictive value and negative predictive value of 44%, 100%, 100% and 81%, respectively. Therefore, the presence of Cho in a PTM may serve as a marker of residual cancer. Furthermore since so few PTMs contain Cho, a percentage change in Cho ratios may not be a useful method for monitoring treatment response.

Evolution of radiation-induced brain injury: MR imaging-based study.

PURPOSE: To evaluate the temporal lobes in patients previously treated for nasopharyngeal carcinoma to provide a better understanding of delayed radiation-induced injury in the brain unaffected by the underlying tumor. MATERIALS AND METHODS: Retrospective analysis of the patient data was approved by the local ethics committee. Informed consent was waived. Magnetic resonance (MR) imaging results in patients with temporal lobe injury (TLI) after receiving radiation for nasopharyngeal carcinoma were analyzed. The appearance and change over time of white matter lesions (WMLs), contrast material-enhanced lesions, and cysts were assessed. The Mann-Whitney U test was used to compare interval time, and the chi(2) and Fisher exact tests were used to compare the pattern of TLI changes. RESULTS: The study group was 124 patients (95 men, 29 women; mean age, 51.4 years) with 192 injured temporal lobes; 62 of these patients with 103 injured temporal lobes underwent follow-up MR imaging at least once (range, one to five examinations). A total of 332 injured temporal lobes were revealed. WMLs, contrast-enhanced lesions, and cysts were present on 332 (100%), 274 (82.5%), and 42 (12.7%) studies, respectively. All contrast-enhanced lesions more than 2 cm in size showed necrosis, and those 3 cm or greater formed a rim-enhanced necrotic mass. WMLs were the only lesion to occur alone, contrast-enhanced lesions were always accompanied by WMLs, and cysts were always accompanied by WMLs and contrast-enhanced lesions. Detection of cysts was significantly later than detection of WMLs and contrast-enhanced lesions (P <.01). Regression or resolution was found in 27 (28%) of 96 WMLs, 37 (39%) of 94 contrast-enhanced lesions, and one (7%) of 15 cysts. CONCLUSION: TLI from radiation is not always an irreversible and progressive process but is one that can regress or resolve at MR imaging. In the evolution of radiation injury, WMLs are seen first and are followed by contrast-enhanced lesions, which have an increasing tendency to become necrotic with increasing size. Cysts are the least frequent manifestation and arise in the late stage of TLI.

[Diagnosis of breast diseases by mammography in combination with MRI].

OBJECT: To study the diagnosis of breast diseases and its clinical application value of mammography in combination with MRI. METHODS: The 46 patients suspected of having breast tumors by mammography, received dynamic contrast-enhanced MRI scanning, and the image features of breast tumors were compared and analyzed. RESULTS: MRI was superior to mammography not only in revealing the location, the shape, the border, internal structure of the mass and its chest-wall invasion, but also in revealing the axillary lymph nodes and the internal mammary lymph nodes and the mammary plugger, and in determining the mass nature in displaying microcalcification. CONCLUSION: Mammography in combination with dynamic contrast-enhanced MRI can help to make an accurate diagnosis of breast diseases.

[An epidemic outbreak of respiratory infection caused by Chlamydia pneumoniae in medical workers].

OBJECTIVE: To investigate the clinical manifestations and the chest imaging characteristics of an epidemic outbreak of respiratory infection caused by Chlamydia pneumoniae (CP). METHODS: A prospective study for CP infection in 15 patients from September 2003 was carried out. Sputum and throat swab specimen were obtained and CP DNA was detected by polymerase chain reaction (PCR). Serum samples were obtained and immunoglobulin G and M (IgG and IgM) of antibodies to CP. pneumoniae were studied by microimmunofluorescence test. Chest X-ray and computed tomography were retrospectively analyzed. RESULTS: All patients presented fever, headache, sore throat, hoarseness, muscular ache, and dry cough. Acute cough was often associated with chest pain. The sputum blood was present in 3 patients (20%). Moist rales were heard in 4 patients. Chest imaging abnormalities were present in 67% (10 patients). The organism was demonstrated in 87% (13 patients) by PCR. The most common imaging abnormalities were unilateral and (or) bilateral multi-focal or solitary alveolar nodular opacities (9 patients). The patchy shadows were found in 2 patients, and pulmonary consolidation associated with the local pulmonary edema in 1 patient. Hilar or mediastinal lymphadenopathy and pleural effusion was not found. CONCLUSIONS: The colony occurrences and similar clinical and chest imaging manifestations are characteristics of an outbreak of respiratory infection caused by CP in medical workers. An outbreak of respiratory infection caused by CP should be differentiated from severe acute respiratory syndrome (SARS).