A new active vitamin D3 analog, eldecalcitol, prevents the risk of osteoporotic fractures--a randomized, active comparator, double-blind study

Background

Eldecalcitol is an analog of 1,25-dihydroxyvitamin D₃ that improves bone mineral density; however, the effect of eldecalcitol on the risk of fractures is unclear. The objective of this study is to examine whether eldecalcitol is superior to alfacalcidol in preventing osteoporotic fractures. This trial is registered with ClinicalTrials.gov, number NCT00144456.

Methods and results

This 3 year randomized, double-blind, active comparator, superiority trial tested the efficacy of daily oral 0.75 μg eldecalcitol versus 1.0 μg alfacalcidol for prevention of osteoporotic fractures. 1054 osteoporotic patients 46 to 92 years old were randomly assigned 1:1 to receive eldecalcitol (n = 528) or alfacalcidol (n = 526). Patients were stratified by study site and serum 25-hydroxyvitamin D level. Patients with low serum 25-hydroxyvitamin D levels (< 50 nmol/L) were supplemented with 400 IU/day vitamin D₃. Primary end point was incident vertebral fractures. Secondary end points included any non-vertebral fractures and change in bone mineral density and bone turnover markers. Compared with the alfacalcidol group, the incidence of vertebral fractures was lower in eldecalcitol group after 36 months of treatment (13.4 vs. 17.5%; hazard ratio, 0.74; predefined 90% confidence interval [CI], 0.56–0.97). Eldecalcitol reduced turnover markers and increased bone mineral density more strongly than alfacalcidol. Eldecalcitol reduced the incidence of three major non-vertebral fractures, which was due to a marked reduction in wrist fractures by a post-hoc analysis (1.1 vs. 3.6%; hazard ratio, 0.29; 95% CI, 0.11–0.77). Among the adverse events, the incidence of increase in serum and urinary calcium was higher in the eldecalcitol group, without any difference in glomerular filtration rate between the two groups.

Conclusions

Eldecalcitol is more efficacious than alfacalcidol in preventing vertebral and wrist fractures in osteoporotic patients with vitamin D sufficiency, with a safety profile similar to alfacalcidol.     

Retrospective evaluation of PSA density for selection of biopsy candidates with prostate specific antigen in the gray zone

PURPOSE: We examined the usefulness of prostate specific antigen density (PSAD) for selection of biopsy candidate with prostate specific antigen levels between 4.1 and 10.0 ng./ml. in prostate cancer screening retrospectively. MATERIALS AND METHODS: The screening was conducted on male candidates in Natori city, aged 55 years or older, for 6 years from 1994 through 1999. We could analyze serum PSA levels and PSA density in 118 men with PSA levels between 4.1 and 10.0 ng./ml. All of 118 men underwent ultrasound guided systematic prostate biopsy regardless of findings of digital rectal examination and transrectal ultrasound. Prostate volume was estimated by transrectal ultrasound measurements using the prolate ellipse formula (pi/6 x length x width x height). PSAD was calculated by dividing serum PSA level by prostate volume. Serum PSA levels were determined by Tandem-R assay. RESULTS: In 118 men, twenty-five men had prostate cancer. There was no significant difference in mean PSA between those with prostate cancer and those without prostate cancer, but the difference was significant in the mean PSA density (mean 0.26 and 0.16, respectively, p < 0.0001). Receiver operating characteristic curves for PSA and PSAD demonstrated superior benefit for PSAD in 118 men. A sensitivity, a specificity, a positive predictive value and a negative predictive value of PSAD cut-off of 0.15 were 88%, 52.7%, 33.3% and 94.2%. PSAD cut-off of 0.18 showed the highest sum of sensitivity and specificity, which gave a sensitivity of 80%, a specificity of 72%, a positive predictive value of 43.5% and a negative predictive value of 93.1%. PSAD cut-off of 0.15 would seem to be preferable to cut-off of 0.18 because of less cancer missing. CONCLUSIONS: Although further studies are needed to determine optimal cut-off value to be used in clinical practice, PASD seems to be useful for the selection of biopsy candidates with PSA levels of 4.1 to 10.0 ng./ml. in the prostate cancer screening.     

Case of retroperitoneal solitary fibrous tumor

Solitary fibrous tumor (SFT) of the retroperitoneal space is rare. We report a case of retroperitoneal tumor, diagnosed as SFT. A 69-year-old woman presented with right lower abdominal swelling, and was referred to our hospital with suspicion of right renal tumor. Abdominal ultrasound and computerized tomography (CT) showed a mass (about 15 x 14 x 10 cm) in the right abdomen. The tumor was thought to be right renal rumor, and right radical nephrectomy was performed. In the excised specimen the tumor was not connected to gastrointestinal tract, peritoneum, or right kidney. The histological and immunohistochemical examination of the specimen revealed SFT. The tumor has malignant potential with partially increased mitotic activity and cellularity in the histological examination. The patient is healthy and without evidence of recurrence or metastasis 26 months from surgery.     

Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) levels, as prognostic indicators in NSCLC.

OBJECTIVES: Non-small cell lung cancer (NSCLC) tissue produces numerous growth factors, which are multifunctional and considered predictive of patient survival. This study sought to evaluate the relationship between concentrations of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) in NSCLC tissue and clinicopathological factors, and determine whether these factors correlate with long-term survival. METHODS: We retrospectively investigated 71 patients with histologically confirmed adenocarcinoma or squamous cell carcinoma of the lung, for whom the primary curative approach was surgery, and who received no chemotherapy or radiotherapy prior to surgery. bFGF, VEGF, HGF were measured in extracts prepared from these 71 frozen tissue samples by ELISA. Five- and 10-year survival was obtained to determine the most important predictors of long-term survival. RESULTS: Among clinicopathological parameters, the mean concentration of bFGF was significantly higher in tissue extracts from cases involving metastatic nodal involvement (87.5+/-69.3 ng/100 mg protein) than in those without nodal involvement (57.6+/-42.5 ng; P<0.05). Levels of VEGF in adenocarcinoma (26.8+/-34.0 ng) were higher than for squamous cell carcinoma (12.2+/-13.8 ng; P<0.05). HGF levels also demonstrated histological differences (14.7+/-7.7 vs. 10.6+/-9.7 ng, P<0.05). bFGF protein levels were basically the same, but showed no statistically significant differences with respect to histological type (72.5+/-55.2 vs. 63.6+/-51.5 ng). Patients with high levels of bFGF or VEGF showed significantly worse survival rates than patients with low levels (P=0.0059; P=0.0134). In particular, high concentrations of both bFGF and VEGF correlated with markedly poor prognosis (P<0.0001). Multivariate analysis indicated that lymph node involvement and levels of bFGF and VEGF were independent prognostic factors in cases of NSCLC (adenocarcinoma or squamous cell carcinoma) involving patients who had undergone curative resection. CONCLUSIONS: Adenocarcinoma associated with lung cancer is regarded to have biological characteristics that distinguish it from squamous cell carcinoma. Node invasion may be associated with bFGF. bFGF and VEGF augment each other and are associated with leading to poor prognosis. The results of this study suggests that effective therapy to block angiogenesis may need to address at least both of these factors in cases of NSCLC.     

Changes in diastolic properties of the regional myocardium during pacing-induced ischemia in human subjects

Mechanisms related to alterations in the diastolic properties of the left ventricle during angina were studied in seven patients with coronary artery disease. Single plane left ventriculograms were obtained using a high fidelity micromanometer-tipped catheter in both the resting state and immediately after rapid cardiac pacing. In all patients, typical anginal pain developed with pacing stress. After atrial pacing, the left ventricular end-diastolic pressure increased from 10 +/- 3 to 21 +/- 7 mm Hg (+/- standard deviation) (p less than 0.005) regardless of the changes in the end-diastolic volume. The ejection fraction was reduced from 59 +/- 10 to 48 +/- 13% (p less than 0.05). The diastolic pressure-volume curves shifted upward in post-pacing beats in four patients, while in three the curves shifted more to the right. The regional myocardial function was expressed in quantitative terms by a radial coordinate system with the origin at the center of gravity of the end-diastolic silhouette. Two representative radial grids for normal and ischemic segments were selected. In the normal segment, the end-diastolic length was augmented by 15% (p less than 0.005) and was associated with a 24% increase in stroke excursion with pacing stress (p less than 0.05). The increase in diastolic pressure was accompanied by comparable increases in end-diastolic length, and the diastolic pressure-length relation moved up to the higher portion of the single curve. In the ischemic segment, the end-diastolic length remained unchanged in the post-pacing beat, but segment shortening was significantly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)     

Skeletal muscle and bone marrow derived stromal cells: A comparison of tenocyte differentiation capabilities

This study investigated the comparative ability of bone marrow and skeletal muscle derived stromal cells (BMSCs and SMSCs) to express a tenocyte phenotype, and whether this expression could be augmented by growth and differentiation factor‐5 (GDF‐5). Tissue harvest was performed on the hind limbs of seven dogs. Stromal cells were isolated via serial expansion in culture. After four passages, tenogenesis was induced using either ascorbic acid alone or in conjunction with GDF‐5. CD44, tenomodulin, collagen I, and collagen III expression levels were compared for each culture condition at 7 and 14 days following induction. Immunohistochemistry (IHC) was performed to evaluate cell morphology and production of tenomodulin and collagen I. SMSCs and BMSCs were successfully isolated in culture. Following tenocytic induction, SMSCs demonstrated an increased mean relative expression of tenomodulin, collagen I, and collagen III at 14 days. BMSCs only showed increased mean relative expression of collagen I, and collagen III at 14 days. IHC revealed positive staining for tenomodulin and collagen I at 14 days for both cell types. The morphology of skeletal muscle derived stromal cells at 14 days had an organized appearance in contrast to the haphazard arrangement of the bone marrow derived cells. GDF‐5 did not affect gene expression, cell staining, or cell morphology significantly. Stromal cells from either bone marrow or skeletal muscle can be induced to increase expression of matrix genes; however, based on expression of tenomodulin and cell culture morphology SMSCs may be a more ideal candidate for tenocytic differentiation. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1710–1718, 2012     

Acute transverse myelitis with urinary retention due to mycoplasma pneumoniae infection: a case report

We report a case of urinary retention complicated with acute transverse myelitis caused by Mycoplasma pneumoniae. A 16-year-old man visited a clinic because of urinary retention, fever, muscle weakness and sensory disturbance of lower extremities. He was referred to our hospital for further examination. He was diagnosed with acute transverse myelitis due to M. pneumoniae infection based on cerebrospinal fluid examination, serum titer of antibody to M. pneumoniae and magnetic resonance imaging. He was treated with corticosteroids for acute myelitis. A urethral catheter was indwellt for urinary retention. His muscle strength and sensory of lower extremities improved after 2 months of treatment, and he was discharged from our hospital. However, since urinary frequency, urge incontinence and weak urinary stream persisted, he was referred to us for further examination. A pressure-flow study examination showed a decreased maximum urinary flow rate and the findings of detrusor sphincter dyssnergia. We diagnosed him with uninhibited bladder and detrusor sphincter dyssnergia. We administered propiverine hydrochloride and imipramine hydrochloride, and his symptoms subsided significantly. Now, (8 months) after this medication, he still has incontinence at night.     

Interim evidence of the renoprotective effect of the angiotensin II receptor antagonist losartan versus the calcium channel blocker amlodipine in patients with chronic kidney disease and hypertension: a report of the Japanese Losartan Therapy Intended for Global Renal Protection in Hypertensive Patients (JLIGHT) Study

Background. Insufficiency of renal function and high blood pressure influence each other and eventually result in life-threatening endstage renal disease. It has been proposed that proteinuria per se is a determinant of the progression of chronic kidney disease (CKD). The therapeutic strategy for patients with proteinuric CKD and hypertension should therefore be targeted with a view not merely toward blood pressure reduction but also toward renoprotection. Methods. We examined the effect of the angiotensin (AT)₁ receptor antagonist losartan and the calcium channel blocker amlodipine, throughout a period of 12 months, on reduction of blood pressure and renoprotection. This was done by assessing amounts of urinary protein excretion, serum creatinine (SCr), and creatinine clearance (CCr) in patients with hypertension (systolic blood pressure [SBP] 140mmHg or diastolic blood pressure [DBP] 90mmHg) and CKD (male, body weight [BW] 60kg: 1.5 SCr < 3.0mg/dl; female or male BW < 60kg: 1.3 SCr < 3.0mg/dl), manifesting proteinuria of 0.5g or more/day. Losartan was administered once daily at doses of 25 to 100mg/day, and amlodipine was given once daily at 2.5 to 5mg/day. No antihypertensive combination therapy was allowed during the first 3-month period. Results. A 3-month interim analysis revealed that, despite there being no difference in blood pressure between the two groups, there was a significant reduction in 24-h urinary protein excretion in the losartan group (n = 43), but there was no change in the amlodipine group (n = 43). Analysis of stratified subgroups with proteinuria of 2g or more/day and less than 2g/day showed that losartan lowered proteinuria by approximately 24% in both subgroups, while amlodipine lowered proteinuria by 10%, but only in the subgroup of less than 2g/day (NS). SCr and CCr did not change throughout the period of 3 months in either group. No severe or fatal adverse event was experienced in either group during the study period. Conclusions. Losartan appeared to be efficacious for renoprotection in patients with proteinuric CKD and hypertension, with the mechanism being independent of its antihypertensive action.     

Spinal cord edema preceding syringomyelia associated with Chiari I malformation--case report

A 38-year-old woman with Chiari I malformation presented with spinal cord edema preceding syringomyelia manifesting as a 5-month history of nuchal pain and numbness of the upper extremities. Magnetic resonance imaging showed spinal cord edema, a poorly defined syrinx at the C-2 to T-2 levels, and distorted cerebellar tonsils. Computed tomography revealed cerebrospinal fluid (CSF) density in the center of spinal cord edema, and positron emission tomography revealed no uptake of L-[methyl-11C]methionine, indicating a non-neoplastic lesion. Craniocervical decompression achieved excellent clinical and neuroradiological outcomes. The success of surgical treatment supports the theory that patients with Chiari I malformation have increased transmural flow of CSF, causing spinal cord edema that progresses to syringomyelia. Early treatment of patients with spinal cord edema is indicated to prevent permanent spinal cord injury due to progressive syringomyelia.     

Primary aortoesophageal fistula secondary to thoracic aneurysm

Aortoesophageal fistula (AEF) secondary to thoracic aneurysm is rare, and is usually fatal without prompt surgical intervention, with few survivors reported. Here we report a case of a 68-year-old woman late-presenting AEF successfully treated by extra-anatomic bypass grafting. Since she had already a mediastinal infection caused by AEF on admission, we performed extra-anatomic bypass grafting from the ascending aorta to the infrarenal aorta, and primary esophageal repair. The extra-anatomic bypass grafting was performed to avoid the risk to secondary graft infection and to decrease the total ishemic time induced by intraoperative aortic clamping, which is necessary when in-situ graft replacement is chosen. Although only 17 cases (including the present case) have been reported as long-term survivors, most have involved in-situ repair of the thoracic aneurysm. To our knowledge, the present case was only the second treated successfully by extra-anatomic bypass grafting. We recommend extra-anatomic bypass grafting for a case with severe infection and prolonged hypoperfusion insult caused by massive bleeding due to rupture in an aneurysm.