Optimal Combination of Effective ANtihypertensives (OCEAN) study: a prospective, randomized, open-label, blinded endpoint trial--rationale, design and results of a pilot study in Japan

There are limited clinical trials examining the efficacy of antihypertensive drug combinations aimed at preventing cardiovascular events. Therefore, we designed a randomized controlled trial using amlodipine as the base drug of a multi-drug regimen, the Optimal Combination of Effective ANtihypertensives (OCEAN) Study, to determine the drug combination that is most efficacious in the prevention of cardiovascular events, such as stroke. The OCEAN Study is a collaborative study between Japan and China, enrolling 20?000 patients and following them for 3 to 4 years. A pilot study was conducted before the full-scale study to confirm the feasibility of the protocol and that the study groups and infrastructures could function properly. A total of 279 Japanese patients were enrolled from 57 participating medical institutions between June and December 2004. Two hundred and sixty-six patients (mean age: 65.9 years) were treated with amlodipine alone. One hundred and fifty-four of these patients (57.9%) did not reach the treatment targets (<140/90?mm?Hg for the elderly and patients with cerebrovascular disease, <130/80?mm?Hg for those with diabetes mellitus, chronic kidney disease or prior myocardial infarction) and a second agent was added. They were randomly allocated into three different treatment groups using a diuretic, a β-blocker or an angiotensin-converting enzyme inhibitor/angiotensin II receptor antagonist. The pilot study showed that the protocol was appropriate, and the inclusion of patients with slightly higher blood pressures was necessary to increase the randomization rate. It also confirmed that we organized properly functioning study groups and infrastructures.     

Impaired regulatory T cell reconstitution in patients with acute graft-versus-host disease and cytomegalovirus infection after allogeneic bone marrow transplantation

To elucidate the correlation between regulatory T cells (Tregs) and acute graft-versus-host disease (aGVHD) or cytomegalovirus infection following allogeneic bone marrow transplantation (allo-BMT), we evaluated either CD4?CD25(high) or FOXP3? Treg-enriched cells in peripheral blood (PB) from 20 patients who received allo-BMT, and in biopsies of skin with aGVHD. Proportions of CD4?CD25(high)FOXP3? cells in total lymphocytes, but not other types of T cells, were lower in patients who eventually developed grades II-IV aGVHD (n = 13) than in others (n = 7, P < 0.001). Proportions of CD62L? cells in CD4?CD25(high) cells at day +30 were lower (P < 0.01) in patients who eventually showed cytomegalovirus viremia (n = 6) than in others (n = 14). Incidence of aGVHD (P < 0.05) or cytomegalovirus viremia (P < 0.05) was higher in patients without these complications, but with lower proportions of PB CD4?CD25(high)FOXP3? cells at day +30 (n = 8) than in others (n = 8). However, in skin with aGVHD (n = 5), there was marked or slightly increased infiltration of CD8? cells (P < 0.001) or CD3?FOXP3? cells (P < 0.05), respectively, when compared with control (n = 5), resulting in threefold higher ratio of CD8?/CD3?FOXP3? cells in aGVHD relative to controls (P < 0.05). Thus, impaired reconstitution of Tregs may be associated with aGVHD and CMV infection. Moreover, imbalance of Tregs and CD8? cells may play a role in aGVHD tissue.     

In vivo pre- and postoperative three-dimensional knee kinematics in unicompartmental knee arthroplasty

Background

Pre- and postoperative knee kinematics in unicompartmental knee arthroplasty (UKA) can be theoretically related to clinical outcome and longevity after UKA with regard to ligament function and the degree of arthritic changes. However, the preoperative knee kinematics of patients indicated for UKA remain to be elucidated, and it is also unclear whether the preoperative kinematics can be maintained by the UKA procedure. The objective of this study was to examine the in vivo pre- and postoperative three-dimensional knee kinematics in UKA while referencing the normal knee kinematics reported in our previous study.

Methods

We analyzed the knee kinematics in 17 knees (14 patients) undergoing UKA via a three-dimensional to two-dimensional registration technique employing femoral condylar translation and femoral axial rotation. The pre- and postoperative knee kinematics during squat motion were evaluated in the same subjects, employing consistent evaluation parameters.

Results

On average, both pre- and postoperative knee kinematics in the range 10–100° of knee flexion demonstrated near-consistent femoral external rotation and anterior translation of the medial condyle and posterior translation of the lateral condyle. However, the mean femoral external rotation angle and the posterior translation of the lateral condyle postoperatively were significantly smaller than the values observed preoperatively.

Discussion

Although the patterns of preoperative knee motion were similar to those seen in normal knees, the magnitude of this motion varied widely between patients, so it was not necessarily representative of normal knees. These variations may be due to the varying degrees of arthritic changes caused by osteoarthritis. Although the patterns of knee kinematics were largely maintained by the UKA procedure, the causes of the significant reductions in the magnitude of motion upon performing the UKA procedure should be investigated in subsequent studies with a larger number of patients.     

Posterior buttress plate with locking compression plate for Hoffa fracture

BackgroundMany difficulties are associated with treating fractures of the posterior condyle of the femur (Hoffa fractures). Anatomical reduction and internal fixation are optimum for such intra-articular fractures. Some surgeons use anteroposterior screws to achieve direct stability. However, screw fixation is not adequate in some cases. To increase stability, we treat Hoffa fractures with a posterior buttress plate; we use a twisted, 1/3 tubular plate at the posterior surface and a supplementary, locking compression plate (LCP) for additional stability.MethodsPatients who had sustained Hoffa fractures between January 2006 and March 2009 were included in this study. Patients comprised three males and two females with a mean age of 73.6 years at the time of surgery. A 3.5-mm 1/3 tubular plate was twisted and applied to the posterolateral aspect of the distal femur. This was combined with an LCP on the distal femur to achieve a rafting effect.ResultsAll fractures were healed within 15 weeks. There were no instances of nonunion, infection, or implant removal. The mean range of motion was ?3° to 121°. Four patients had no pain in the treated limb and one had mild pain on weight bearing. The average Oxford Knee Score was 44.6 points. All patients achieved satisfactory joint function and regained their walking ability with good clinical results.ConclusionsImproved stability associated with this technique enables patients to begin range-of-motion training and return to their normal activities sooner; this resulted in good outcome.     

Is Memorial Sloan-Kettering Cancer Center risk classification appropriate for Japanese patients with metastatic renal cell carcinoma in the cytokine era?

ObjectivesWe investigated the prognosis of Japanese patients with metastatic renal cell carcinoma (RCC), and analyzed the validity of Memorial Sloan-Kettering Cancer Center (MSKCC) risk classification.Materials and methodsThe endpoint of the present study was overall survival. Relationships between overall survival and potential prognostic factors were assessed using the Cox proportional hazard model with a step-wise procedure. Prognostic assessment was also performed according to the MSKCC risk classification. The predictive accuracy of the MSKCC risk classification was measured employing the concordance index.ResultsThe median survival for all patients was 22 months (95% CI, 19–28 months). The eight factors were identified as independent prognostic factor; time from initial diagnosis to metastasis, low hemoglobin (Hb), lactate dehydrogenase (LDH), corrected serum calcium (cCa), C-reactive protein (CRP), and the presence or absence of liver metastasis, bone metastasis, and lymph node metastasis. When the MSKCC risk classification was applied to patients, the median overall survival was not reached and 26 and 10 months in the patients classified as favorable, intermediate, and poor risk, respectively. The c-index was 0.73.ConclusionsThe prognosis of Japanese metastatic renal cell carcinoma patients may be better than that of previous studies from North America or Europe. Although there are some differences in the rate of patients in the risk groups and survival time by risk group between these patients, the MSKCC risk classification may be applicable for Japanese patients with metastatic renal cell carcinoma.     

Autosomal dominant polycystic kidney disease: recent advances in pathogenesis and potential therapies

Autosomal dominant polycystic kidney disease (ADPKD) is the most common progressive hereditary kidney disease. In 85–90 % of cases, ADPKD results from a mutation in the PKD1 gene, and the other 10–15 % of the cases are accounted for by mutations in PKD2. PKD1 and PKD2 encode polycystin-1 and polycystin-2. Polycystin-1 may be a receptor that controls the channel activity of polycystin-2 as part of the polycystin signaling complex. ADPKD is characterized by the progressive development of fluid-filled cysts derived from renal tubular epithelial cells that gradually compress the parenchyma and compromise renal function. In recent years, considerable interest has developed in the primary cilia as a site of the proteins that are involved in renal cystogenesis. The pathological processes that facilitate cyst enlargement are hypothesized to result from two specific cellular abnormalities: (1) increased fluid secretion into the cyst lumen and (2) inappropriately increased cell division by the epithelium lining the cyst. Since there is no clinically approved specific or targeted therapy, current practice focuses on blood pressure control and statin therapy to reduce the cardiac mortality associated with chronic kidney disease. However, recent advances in our understanding of the pathways that govern renal cystogenesis have led to a number of intriguing possibilities in regard to therapeutic interventions. The purpose of this article is to review the pathogenesis of renal cyst formation and to review novel targets for the treatment of ADPKD.