Satoru Ebihara

Impact of Nocturia on Bone Fracture and Mortality in Older Individuals: A Japanese Longitudinal Cohort Study

PURPOSE We evaluated the association of nocturia with fracture and death in a large, community based sample of Japanese individuals 70 years old or older. MATERIALS AND METHODS The baseline in this population based study was determined in 2003 by an extensive health interview with each participant. In this study we followed 784 individuals with a mean ± SD age of 76.0 ± 4.6 years (range 70 to 97). Information on mortality and fracture during the study period was provided by the National Health Insurance system and details on fractures were collected from medical records. We compared the risk of bone fracture and death with or without nocturia in a multivariate Cox proportional hazard model. RESULTS Nocturia (2 or greater voids per night) was present in 359 of the 784 participants (45.7%). Fracture was observed in 41 cases, including 32 fall related cases. For all fractures and fall related fractures with nocturia the HR was 2.01 (95% CI 1.04-3.87) and 2.20 (95% CI 1.04-4.68, each p = 0.04). Death occurred in 53 cases. The mortality rate in individuals with nocturia was significantly higher than in those without nocturia. For mortality in patients with nocturia the age-gender adjusted HR was 1.91 (95% CI 1.07-3.43, p = 0.03). Even when further adjusted for diabetes, smoking status, history of coronary disease, renal disease and stroke, tranquilizers, hypnotics and diuretics, the positive relationship was unchanged (HR 1.98, 95% CI 1.09-3.59, p = 0.03). CONCLUSIONS During a 5-year observation period elderly individuals with nocturia were at greater risk for fracture and death than those without nocturia.

Randomized Phase II Trial Comparing Nitroglycerin Plus Vinorelbine and Cisplatin With Vinorelbine and Cisplatin Alone in Previously Untreated Stage IIIB/IV Non–Small-Cell Lung Cancer

PURPOSE To investigate the efficacy and safety of nitroglycerin plus vinorelbine and cisplatin in patients with previously untreated stage IIIB/IV non-small-cell lung cancer (NSCLC) as the experimental arm for the next phase III trial. PATIENTS AND METHODS One hundred twenty patients with stage IIIB/IV NSCLC were randomly assigned to vinorelbine 25 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1, with transdermally applied nitroglycerin (25 mg/patient daily for 5 days; arm A) or with placebo patch (arm B) every 3 weeks for a maximum of four cycles in a double-blind and controlled trial. Primary efficacy end points were the best confirmed response rate and time to disease progression (TTP). RESULTS The response rate in arm A (72%; 43 of 60 patients) was significantly higher than that for patients in arm B (42%; 25 of 60 patients; P < .001). Median TTP in arm A was longer than that in arm B (327 v 185 days). No severe adverse effect was recognized for either arm. The rate of grade 1 to 2 headache in arm A (30%; 18 of 60 patients) was significantly higher than that in arm B (2%; one of 60 patients; P < .001, chi(2) test). CONCLUSION Use of nitroglycerin combined with vinorelbine and cisplatin may improve overall response and TTP in patients with stage IIIB/IV NSCLC. The arm A regimen is being evaluated in a large phase III trial.

Adenovirus-Mediated Utrophin Gene Transfer Mitigates the Dystrophic Phenotype of mdx Mouse Muscles

Utrophin is a close homolog of dystrophin, the protein whose mutations cause Duchenne muscular dystrophy (DMD). Utrophin is present at low levels in normal and dystrophic muscle, whereas dystrophin is largely absent in DMD. In such cases, the replacement of dystrophin using a utrophin gene transfer strategy could be more advantageous because utrophin would not be a neoantigen. To establish if adenovirus (AV)-mediated utrophin gene transfer is a possible option for the treatment of DMD, an AV vector expressing a shortened version of utrophin (AdCMV-Utr) was constructed. The effect of utrophin overexpression was investigated following intramuscular injection of this AV into mdx mice, the mouse model of DMD. When the tibialis anterior (TA) muscles of 3- to 5-day-old animals were injected with 5 microl of AdCMV-Utr (7.0 x 10(11) virus/ml), an average of 32% of fibers were transduced and the transduction level remained stable for at least 60 days. The presence of utrophin restored the normal histochemical pattern of the dystrophin-associated protein complex at the cell surface and resulted in a reduction in the number of centrally nucleated fibers. The transduced fibers were largely impermeable to the tracer dye Evans blue, suggesting that utrophin protects the surface membrane from breakage. In vitro measurements of the force decline in response to high-stress eccentric contractions demonstrated that the muscles overexpressing utrophin were more resistant to mechanical stress-induced injury. Taken together, these data indicate that AV-mediated utrophin gene transfer can correct various aspects of the dystrophic phenotype. However, a progressive reduction in the number of transduced fibers was observed when the TA muscles of 30- to 45-day-old mice were injected with 25 microl of AdCMV-Utr. This reduction coincides with a humoral response to the AV and transgene, which consists of a hybrid mouse-human cDNA.

Capsaicin Troche for Swallowing Dysfunction in Older People

Objectives: To determine whether oral capsaicin troche supplementation with every meal upregulates the impairment of upper respiratory protective reflexes such as the swallowing reflex and the cough reflex.

A randomized trial of olfactory stimulation using black pepper oil in older people with swallowing dysfunction

OBJECTIVES: To determine the effect of olfactory stimulation with volatile black pepper oil (BPO) on risk factors for pneumonia.

Green tea consumption is associated with depressive symptoms in the elderly

BACKGROUND Green tea is reported to have various beneficial effects (eg, anti-stress response and antiinflammatory effects) on human health. Although these functions might be associated with the development and progression of depressive symptoms, no studies have investigated the relation between green tea consumption and depressive symptoms in a community-dwelling population. OBJECTIVE The aim of this study was to investigate the relations between green tea consumption and depressive symptoms in elderly Japanese subjects who widely consumed green tea. DESIGN We conducted a cross-sectional study in 1058 community-dwelling elderly Japanese individuals aged >or=70 y. Green tea consumption was assessed by using a self-administered questionnaire, and depressive symptoms were evaluated by using the 30-item Geriatric Depression Scale with 2 cutoffs: 11 (mild and severe depressive symptoms) and 14 (severe depressive symptoms). If a participant was consuming antidepressants, he or she was considered to have depressive symptoms. RESULTS The prevalence of mild and severe and severe depressive symptoms was 34.1% and 20.2%, respectively. After adjustment for confounding factors, the odds ratios (95% CI) for mild and severe depressive symptoms when higher green tea consumption was compared with green tea consumption of <or=1 cup/d were as follows: 2-3 cups green tea/d (0.96; 95% CI: 0.66, 1.42) and >or=4 cups green tea/d (0.56; 95% CI: 0.39, 0.81) (P for trend: 0.001). Similar relations were also observed in the case of severe depressive symptoms. CONCLUSION A more frequent consumption of green tea was associated with a lower prevalence of depressive symptoms in the community-dwelling older population.

Macrophage Colony-Stimulating Factor Induces Vascular Endothelial Growth Factor Production in Skeletal Muscle and Promotes Tumor Angiogenesis

Although M-CSF has been used for myelosuppression due to chemotherapy in patients with solid tumors, the effect of exogenous M-CSF on tumor angiogenesis has not been studied. In this study we showed that M-CSF has the ability to accelerate solid tumor growth by enhancing angiogenesis with a novel mechanism. M-CSF accelerated intratumoral vessel density in tumors inoculated into mice, although it did not accelerate the proliferation of malignant cells and cultured endothelial cells in vitro. In both the absence and the presence of tumors, M-CSF significantly increased the circulating cells that displayed phenotypic characteristics of endothelial progenitor cells in mice. Moreover, M-CSF treatment induced the systemic elevation of vascular endothelial growth factor (VEGF). VEGFR-2 kinase inhibitor significantly impaired the effect of M-CSF on tumor growth. In vivo, M-CSF increased VEGF mRNA expression in skeletal muscles. Even after treatment with carageenan and anti-CD11b mAb in mice, M-CSF increased VEGF production in skeletal muscles, suggesting that systemic VEGF elevation was attributed to skeletal muscle VEGF production. In vitro, M-CSF increased VEGF production and activated the Akt signaling pathway in C2C12 myotubes. These results suggest that M-CSF promotes tumor growth by increasing endothelial progenitor cells and activating angiogenesis, and the effects of M-CSF are largely based on the induction of systemic VEGF from skeletal muscles.

Modulation of Starling Forces and Muscle Fiber Maturity Permits Adenovirus-Mediated Gene Transfer to Adult Dystrophic (mdx) Mice by the Intravascular Route

Duchenne muscular dystrophy (DMD) and other inherited myopathies lead to progressive destruction of most skeletal muscles in the body, including those responsible for maintaining respiration. DMD is a fatal disorder caused by defects in the dystrophin gene. Recombinant adenovirus vectors (AdV) are considered a promising means for therapeutic delivery of a functional dystrophin gene to DMD muscles. If AdV-mediated dystrophin gene replacement in DMD is to be successful, development of a systemic delivery method for targeting the large number of diseased muscles will be required. In this study we investigated two major factors preventing efficient AdV-mediated gene transfer to skeletal muscles of adult animals after intravascular AdV administration: (1) an inability of AdV particles to breach the endothelial barrier and enter into contact with myofibers, and (2) a relatively nonpermissive myofiber population for AdV infection due at least in part to insufficient levels of the coxsackie/adenovirus attachment receptor (CAR). On the basis of established principles governing the transendothelial flux of macromolecules, we further hypothesized that an alteration in Starling forces (increased hydrostatic and decreased osmotic pressures) within the intravascular compartment would facilitate AdV transendothelial flux via convective transport. In addition, experimental muscle regeneration was employed to increase the prevalence of immature myofibers in which CAR expression is upregulated. Here we report that by employing the above-described strategy, high-level heterologous reporter gene expression was achievable in hindlimb muscles of normal rats as well as dystrophic (mdx) mice (genetic homolog of DMD) after a single intraarterial injection of AdV. Microsphere studies confirmed enhanced transport into muscle of fluorescent tracer particles in the size range of AdV, and there was a high concordance between CAR upregulation and myofiber transduction after intraarterial AdV delivery. Furthermore, in mdx mice examined 10 days after intraarterial AdV delivery, the aforementioned procedures had no adverse effects on the force-generating capacity of targeted muscles. These findings have implications for eventual AdV-mediated gene therapy of generalized skeletal muscle diseases such as DMD using a systemic intraarterial delivery approach.

Role of ephrinB2 in nonproductive angiogenesis induced by Delta-like 4 blockade.

Delta-like 4 (DLL4) is one of the Notch ligands and plays an important role in vascular development. DLL4 blockade inhibits tumor growth by promoting nonproductive angiogenesis, which is characterized by an increase in vascular density and decrease in tissue perfusion. However, a detailed mechanism remains unclear. In this study, newly developed neutralizing antibodies against mouse and human DLL4 were used to investigate the possible involvement of VEGF-DLL4-ephrinB2 cascade in nonproductive angiogenesis caused by DLL4 blockade. DLL4 blockade and soluble ephrinB2 treatment suppressed tumor growth and induced nonproductive angiogenesis. DLL4 was expressed in subcutaneous tumors, and DLL4 blockade suppressed ephrinB2 expression in the tumors. DLL4 blockade significantly promoted human umbilical vein endothelial cell (HUVEC) proliferation in vitro, and the effect was additive to that of VEGF. Both DLL4 blockade and VEGF significantly increased cord length and branch points in a tubular formation assay. Expression of ephrinB2 in HUVECs was enhanced by VEGF alone, and the enhancement was inhibited by DLL4 blockade. Moreover, when we studied the effect of ephrinB2 RNA interference on HUVEC tubular formation, knockdown of ephrinB2 mimicked the effect of DLL4. These results suggest that ephrinB2 plays a crucial role in nonproductive angiogenesis caused by DLL4 blockade.

Effect of temperature on swallowing reflex in elderly patients with aspiration pneumonia

To the Editor: We read with interest the study by Ricauda et al. describing a home hospital (HH) model of care for patients with acute stroke because it highlights important issues related to defining a HH. A wide variety of models of care has been described in the international literature under the HH umbrella, engendering controversy over the definition of HH and the effectiveness of the model. These models include the outpatient infusion centerwhere patients receive an intravenous infusion or other treatment; the physicians’ office intravenous service where patients predominantly self-infuse their medications and are reviewed in physicians’ offices; the delivery of home-based care by hospital, or hospital contracted, staff or in the United States by a home health agency to patients in their own homes; early discharge schemes, mostly for postsurgical patients in which patients early in the postoperative period are discharged home and receive postoperative nursing supervision and skilled therapies at home, again with little organized input from physicians; and a clinical unit model that delivers acute hospital-level medical care in the patient’s home and substitutes entirely for an acute hospital admission. Physician and nursing care are provided in the home, as well as appropriate diagnostic and therapeutic care and technologies. The study of HH for acute stroke by Ricauda et al. is an excellent example of a clinical unit model of HH. This HH model possessed three elements we consider to be key features that define a HH. (1) It provides care that substitutes entirely for an inpatient acute hospital admission. (2) It provides an intensity of care, including medical and nursing care, similar to that provided in the hospital appropriate to the severity of the illness treated. (3) It provides care that cannot be provided by usual community-based home care services. Defining HH in this manner relates to the underlying rationale of the model. The main reasons for developing HH include reducing iatrogenic complications including functional decline, honoring patients’ wishes for their care, and reducing expenses. Given this, substitution for an acute hospital inpatient stay is essential in satisfying the HH care model to its fullest extent. Postdischarge programs and nursing programs that do not substitute for a hospital admission entirely expose the patient to the acute hospital environment, may not satisfy patient preference to avoid the hospital, and probably are not as economically efficient as possible. To substitute entirely for an inpatient admission, HH should provide an intensity of care similar to that provided in the hospital to ensure proper evaluation and treatment of the acutely ill patient. This means that 24-hour access to hospital-level medical and nursing care and appropriate diagnostic and therapeutic modalities must be available to the care of the patient. This has generally not been available in the community setting or in many models claiming to be HH. Provision of HH needs to be care that typical community-based home care services cannot provide. HH programs that become blurred with other community-based programs run a high risk of subsequent failure, simply because the skills and organization are different from those required for non-HH community-based care provision. In terms of economics, labeling typical community-based home care services as HH care may simply undermine the economic rationale for the model if expensive HH care is provided to patients who do not require it. Finally, in terms of research and evaluation, blurred boundaries between HH and more typical home care services may result in substantial heterogeneity of patients and care requirements and ensure that outcome studies trend towards equivalence. We hope that focusing the definition of HH will facilitate further development and research on this emerging model of care.