Review of sick house syndrome

'Sick house syndrome' (SHS) is a health issue that closely resembles sick building syndrome (SBS) that had occurred in European countries. The aim of this review is to clarify the characteristics of SHS by reviewing previous reports rigorously. We propose the definition of SHS as "health impairments caused by indoor air pollution, regardless of the place, causative substance, or pathogenesis". Cases of SBS are reported to occur predominantly in offices and sometimes schools, whereas those of SHS are usually found in general dwellings. In many cases, SHS is caused by biologically and/or chemically polluted indoor air. Physical factors might affect the impairments of SHS in some cases. It is considered that symptoms of SHS develop through toxic, allergic and/or some unknown mechanisms. Psychological mechanisms might also affect the development of SHS. It is still unclear whether SBS and SHS are very close or identical clinical entities, mostly because a general agreement on a diagnostic standard for SHS has not been established. Previous research gradually clarified the etiology of SHS. Further advances in research, diagnosis, and treatment of SHS are warranted with the following measures. Firstly, a clinical diagnostic standard including both subjective and objective findings must be established. Secondly, a standard procedure for assessing indoor air contamination should be established. Lastly, as previous research indicated multiple causative factors for SHS, an interdisciplinary approach is needed to obtain the grand picture of the syndrome.     

On-treatment C-reactive protein control could predict response to subsequent anti-PD-1 treatment in metastatic renal cell carcinoma

Objective

The aim of this study was to evaluate the clinical significance of the on-treatment C-reactive protein (CRP) status during systemic treatment as the predictive marker for the response of subsequent nivolumab monotherapy in patients with refractory metastatic renal cell carcinoma (mRCC).

Patients and methods

A total of 73 mRCC patients treated with nivolumab were retrospectively reviewed. We evaluated the serum CRP levels before and after molecular-targeted treatments. Patients whose CRP did not exceed baseline value were defined as the CRP-control group and the others were defined as the CRP-progression group. The clinical impact of CRP-control on the efficacy of nivolumab was assessed.

Results

Twenty-four patients (33%) were categorized into the CRP-control group. The CRP-control group patients (median PFS not reached) had significantly longer PFS than the CRP-progression group (median PFS 11.9 months, 95% confidence interval, CI 4.1–19.8, p?=?0.038). The CRP-control group had a tendency of longer OS from nivolumab initiation than the CRP-progression group (p?=?0.071). By multivariate analysis, the on-treatment CRP-control was the independent predictive factor for PFS (hazard ratio HR 0.37, 95% CI 0.14–0.99, p?=?0.047).

Conclusion

The on-treatment CRP-control could be the predictive factor for the efficacy of nivolumab in refractory mRCC patients.

     

The clinicopathological characteristics of muscle-invasive bladder recurrence in upper tract urothelial carcinoma

This study aimed to clarify the clinical characteristics and oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who developed muscle-invasive bladder cancer (MIBC) after radical nephroureterectomy (RNU). We identified 966 pTa-4N0-2M0 patients with UTUC who underwent RNU and clarified the risk factors for MIBC progression after initial intravesical recurrence (IVR). We also identified 318 patients with primary pT2-4N0-2M0 MIBC to compare the oncological outcomes with those of patients with UTUC who developed or progressed to MIBC. Furthermore, immunohistochemical examination of p53 and FGFR3 expression in tumor specimens was performed to compare UTUC of MIBC origin with primary MIBC. In total, 392 (40.6%) patients developed IVR after RNU and 46 (4.8%) developed MIBC at initial IVR or thereafter. As a result, pT1 stage on the initial IVR specimen, concomitant carcinoma in situ on the initial IVR specimen, and no intravesical adjuvant therapy after IVR were independent factors for MIBC progression. After propensity score matching adjustment, primary UTUC was a favorable indicator for cancer-specific death compared with primary MIBC. Subgroup molecular analysis revealed high FGFR3 expression in non-MIBC and MIBC specimens from primary UTUC, whereas low FGFR3 but high p53 expression was observed in specimens from primary MIBC tissue. In conclusion, our study demonstrated that patients with UTUC who develop MIBC recurrence after RNU exhibited the clinical characteristics of subsequent IVR more than those of primary UTUC. Of note, MIBC subsequent to UTUC may have favorable outcomes, probably due to the different molecular biological background compared with primary MIBC.     

Production of dengue 2 envelope domain III in plant using TMV-based vector system

The envelope protein of dengue virus is the major protein involved in host cell receptor binding for viral entry and induction of immunity. A gene fragment encoding domain III of the dengue 2 envelope protein (D2EIII, amino acids 298-400) was successfully expressed in Nicotinana benthamiana plant using a tobacco mosaic virus (TMV)-based transient expression system. The N-terminal 5' untranslated region-omega sequence located upstream of D2EIII increased protein production in infected plant tissues. The recombinant protein was reactive with anti-D2EIII polyclonal and anti-His tag antibodies. The intramuscular immunization of mice with D2EIII induced the production of the anti-dengue virus antibody. The induced antibody demonstrated neutralizing activity against dengue type 2 virus. The result indicates that the TMV expression system produces the dengue virus antigen in plant, which possesses appropriate antigenicity and immunogenicity.     

Effect of lactulose on calcium and magnesium absorption: a study using stable isotopes in adult men

To evaluate the effect of lactulose on calcium (Ca) and magnesium (Mg) absorption, we performed a clinical trial with a double-blind, randomized, crossover design in 24 healthy adult male volunteers. The absorptions of Ca and Mg were evaluated by a single-labeling method using stable isotopes. The test foods, containing lactulose at a dose of 0 g (placebo), 2 g (low-dose), or 4 g (high-dose) together with 300 mg of Ca containing 20 mg of 44Ca, and 150 mg of Mg containing 28 mg of 25Mg, were administered orally. Urine samples were collected for 8 h after the ingestion of the test food. The ratios of stable isotopes in urine (44Ca/40Ca and 25Mg/24Mg) were measured by ICP-MS (inductively coupled plasma-mass spectrometry). The urinary stable-isotopes ratios (44Ca/40Ca and 25Mg/24Mg) increased with lactulose dosage. Significant differences were observed in the Ca ratio between placebo and high-dose lactulose (p<0.01), and in the Mg ratio between placebo and low-dose lactulose and between placebo and high-dose lactulose (p<0.01). Lactulose ingestion did not change the levels of bone-resorption markers (type I collagen cross-linked N-telopeptide and deoxypyridinoline) in urine. The test foods did not cause any side effects. This study demonstrates that lactulose enhances the absorptions of Ca and Mg in adult men.     

Effects of alfacalcidol on cancellous and cortical bone mass in rats treated with glucocorticoid: a bone histomorphometry study

The beneficial effects of alfacalcidol (ALF) on bone mass, bone formation, and bone resorption have been established in ovariectomized rats. Our previous studies showed that high-dose glucocorticoid (GC) administration (methylprednisolone sodium succinate, 5.0 mg/kg, s.c., 3 times a week) for 4 wk induced cancellous osteopenia without significantly affecting cortical bone mass in Sprague-Dawley rats, and that high-dose GC administration for 8 wk also resulted in cortical osteopenia. The purpose of the present study was to examine the effects of ALF on cancellous and cortical bone mass in GC-treated rats. Forty female Sprague-Dawley rats, 3 mo of age, were randomized by the stratified weight method into four groups of 10 rats each, as follows: age-matched control group (CON); 8-wk GC administration with administration of vehicle during the latter 4 wk of treatment (GC group); 8-wk GC administration with administration of a low dose of ALF (0.08 Ag/kg) during the latter 4 wk of treatment (low-dose ALF group); 8-wk administration of GC with administration of a high dose ofALF (0.16 microg/kg) during the latter 4 wk of treatment (high-dose ALF group). The GC (methylprednisolone sodium succinate, 5.0 mg/kg) was administered subcutaneously 3 times a week, and ALF was administered orally 5 times a week. At the end of the experiment, static and dynamic bone histomorphometric analyses were performed on cancellous bone of the proximal tibial metaphysis and cortical bone of the tibial diaphysis. Eight-week GC administration resulted in loss of the cancellous bone volume/total tissue volume (BV/TV) and percent cortical area (Ct Ar) as a result of decreased trabecular bone formation, increased trabecular and endocortical bone resorption, and decreased periosteal bone formation. Low-dose ALF restored the cancellous BV/TV by mildly suppressing bone resorption and restoring bone formation, whereas high-dose ALF increased it beyond the value observed in the age-matched controls by strongly suppressing bone resorption and markedly increasing bone formation. Both low- and high-dose ALF prevented the GC-induced reduction of the percent Ct Ar by increasing periosteal bone formation and suppressing endocortical bone resorption. The effects of ALF on cancellous bone mass, bone formation, and bone resorption were all dose-dependent. The present study showed the beneficial effects of ALF on cancellous and cortical bone mass in GC-treated rats.     

Evaluation of the Efficacy of Sorafenib on Overall Survival in Patients with Hepatocellular Carcinoma using FT Rate: A Devised Index

Introduction

Transcatheter arterial chemoembolization (TACE) is the first-line treatment for intermediate stage hepatocellular carcinoma (HCC) and prolongs survival in HCC patients. However, repeated TACE results in diminished therapeutic response. In addition, the superiority of sorafenib to TACE monotherapy or combined therapy in patients with HCC is still controversial. The prognosis of HCC has many variables and, thus, the effect of a specific treatment is difficult to evaluate. The frequency of treatments per year (FT rate) used in this study was obtained by dividing the total number of radiofrequency ablations and TACE or transcatheter arterial infusion treatments by the years of survival. The aim of this study was to evaluate the overall survival (OS) of TACE versus sorafenib using the FT rate.

Methods

We compared the OS of patients with recurrence of HCC receiving repeated TACE monotherapy (CON) with those receiving therapy switched from TACE to sorafenib (SOR). In addition, a one-to-one FT rate matching cohort consisting of matched SOR (mSOR) and matched CON (mCON) was determined using the propensity score matching method, and OS in the cohort was evaluated. Factors influencing survival were evaluated using Cox proportional hazard regression analysis in all patients and the FT rate matched cohort.

Results

In the FT rate matched cohort, the cumulative survival rate was significantly higher in the mSOR group compared with the mCON group. Multivariate regression analysis of the FT rate matched cohort showed the FT rate and sorafenib to be significant variables for survival with a hazard ratio (HR) of 2.86 (p < 0.001) and 0.42 (p = 0.008), respectively.

Conclusion

Early switching from TACE to sorafenib therapy may prolong OS in HCC patients unresponsive to TACE. The present study indicates that the FT rate is potentially a useful index in evaluating the outcome for patients at various stages and treatment regimens.

Funding

Bayer Yakuhin, Ltd.

     

p53 and PTEN/MMAC1/TEP1 gene therapy of human prostate PC-3 carcinoma xenograft, using transferrin-facilitated lipofection gene delivery strategy

We previously reported that supplementation of a cationic liposome with transferrin (Tf) greatly enhanced lipofection efficiency (P.-W. Cheng, Hum. Gene Ther. 1996;7:275-282). In this study, we examined the efficacy of p53 and PTEN tumor suppressor gene therapy in a mouse xenograft model of human prostate PC-3 carcinoma cells, using a vector consisting of dimyristoyloxypropyl-3-dimethylhydroxyethyl ammonium bromide (DMRIE)-cholesterol (DC) and Tf. When the volume of the tumors grown subcutaneously in athymic nude mice reached 50-60 mm(3), three intratumoral injections of the following four formulations were performed during week 1 and then during week 3: (1) saline, (2) DC + Tf + pCMVlacZ, (3) DC + Tf + pCMVPTEN, and (4) DC + Tf + pCMVp53 (standard formulation). There was no significant difference in tumor volume and survival between group 1 and group 2 animals. As compared with group 1 controls, group 3 animals had slower tumor growth during the first 3 weeks but thereafter their tumor growth rate was similar to that of the controls. By day 2 posttreatment, group 4 animals had significantly lower tumor volume relative to initial tumor volume as well as controls at the comparable time point. Also, animals treated with p53 survived longer. Treatment with DC, Tf, pCMVp53, DC + pCMVp53, or Tf + pCMVp53 had no effect on tumor volume or survival. Expression of p53 protein and apoptosis were detected in tumors treated with the standard formulation, thus associating p53 protein expression and apoptosis with efficacy. However, p53 protein was expressed in only a fraction of the tumor cells, suggesting a role for bystander effects in the efficacy of p53 gene therapy. We conclude that intratumoral gene delivery by a nonviral vector consisting of a cationic liposome and Tf can achieve efficacious p53 gene therapy of prostate cancer.     

The relationship between anteroposterior stability and medial–lateral stability of the bi-cruciate stabilized total knee arthroplasty

Background

Acquisition of appropriate anteroposterior (AP) stability depends on the prosthetic design and intraoperative soft tissue handling. A bi-cruciate stabilized (BCS) total knee arthroplasty (TKA) has a two cam-post mechanism, which substitutes for the anterior cruciate ligament and posterior cruciate ligament (PCL). Therefore, appropriate AP stability is expected. Because the PCL is sacrificed during BCS TKA, medial stability and lateral stability are thought to be important factors to determine AP stability. However, no previous study has reported AP stability after BCS TKA and the relationship between AP and medial–lateral stability.