Tiotropium, a novel muscarinic M3 receptor antagonist, improved symptoms of chronic obstructive pulmonary disease complicated by chronic heart failure.

A 77-year-old man was referred to hospital because of dyspnea on exertion. Although the patient had been fully medicated for chronic heart failure (CHF) caused by hypertensive heart disease, the echo-estimated left ventricular end-diastolic pressure (LVEDP) and brain natriuretic peptide (BNP) level had continued to be high for at least 2 years. Pulmonary functional examination revealed concomitant chronic obstructive pulmonary disease (COPD). Because beta-agonists were expected to exacerbate the CHF, inhalation of tiotropium, a non-beta-adrenergic bronchodilator and novel M3 muscarinic receptor antagonist, was used to treat the COPD. Not only did the pulmonary function improved but the treatment also safely ameliorated CHF signs including LVEDP and plasma BNP.     

Effects of aging on vasopressin production in a kindred with autosomal dominant neurohypophyseal diabetes insipidus due to the DeltaE47 neurophysin mutation

Postmortem examinations of the hypothalamus of patients with autosomal dominant neurohypophyseal diabetes insipidus (adNDI), which have been reported only on persons dying between the ages of 37-87 yr, reveal the presence of the arginine vasopressin (AVP)-producing parvocellular neurons but the absence of 95% of the expected AVP-producing magnocellular neurons. To determine whether the clinical course of adNDI is compatible with the hypothesis that the neuropathologic findings are attributable to a progressive loss of magnocellular neurons beginning in early life, we performed posterior pituitary magnetic resonance imaging and water deprivation tests, including plasma ACTH measurements, on 17 affected members of a kindred with the deltaE47 neurophysin mutation whose ages ranged from 3 months to 54 yr. Nine adult nonaffected members (ages, 20-56 yr) underwent these tests as controls. All six children undergoing magnetic resonance imaging demonstrated a posterior pituitary hyperintense signal (PPHS). Eight of nine affected adults showed an absent or barely visible PPHS, whereas eight of nine age-matched nonaffected adults produced a normal size PPHS. During water deprivation tests, infants concentrated their urine normally, and a 3-month-old infant produced a high plasma AVP level of 15.7 pmol/liter. By school age, affected children were no longer able to concentrate their urine or prevent hypernatremia. Affected adults became dehydrated; their median plasma AVP level was less than 1.0 pmol/liter, but their median fasting plasma ACTH was 2-fold greater than the level of nonaffected adults (10.0 vs. 5.0 pmol/liter; P = 0.008). These results suggest that adNDI is a progressive disease associated with chronic loss of the magnocellular neurons that supply AVP to the posterior pituitary but preservation of the parvocellular neurons that supply AVP and CRH to the median eminence and stimulate ACTH production during hypernatremia.     

Surgical management of endocrine tumor of the pancreas in Japan

Endocrine tumor of the pancreas is potentially malignant. A multicenter analysis of these tumors was conducted to clarity the present status of their surgical management and the subsequent long-term surgical results. The Japan pancreatoduodenectomy (JPD) study group carried out the study; 368 patients were enrolled and variables related to tumor characteristics, surgery, and survival were retrospectively analyzed. There were 222 patients with functioning tumor and 143 patients with nonfunctioning tumor. Malignant tumor was found in 140 of 368 (38%) of the patients, and 63/140 (45%) of these patients had metastatic lesion; the most common site of the metastasis was liver 34/136 (25%), followed by regional lymph nodes 26/136 (19%). Pancreatic resection was performed in 91% of patients with nonfunctional tumor and in 83% of those with malignant tumor, and 73% of the pancreatic resections were done with lymph node dissection. The overall 5-year actuarial survival rate was 76% in patients with malignant tumor. The actuarial 5-year survival rate was 93% in the patients without metastasis and 83% in patients who received curative resection. Multivariate analysis showed that the presence or absence of synchronous metastasis was the sole significant prognostic factor. The results suggest that: (i) malignant endocrine tumor of the pancreas is a curable malignancy when pancreatic resection with lymph node dissection is adopted and (ii) that synchronous metastasis is the dominant prognostic factor.     

Balloon-occluded retrograde transvenous obliteration improves liver function in patients with cirrhosis and portal hypertension

BACKGROUND AND AIM: Balloon-occluded retrograde transvenous obliteration (B-RTO) is a novel therapeutic method for the treatment of large gastric fundal varices with spontaneous splenorenal shunt (SRS). However, the effects of B-RTO on liver function remain unknown. METHODS: Fourteen patients with portal hypertension and gastric varices with SRS were studied, consisting of four patients with acute bleeding, five with high-risk varices, and five with refractory portosystemic encephalopathy. Hepatic venous catheterization was performed to evaluate hepatic blood flow and liver function using the continuous indocyanine green (ICG) infusion method. To assess the metabolic activity of the hepatocyte, the intrinsic clearance of ICG was calculated. In all patients, endoscopic study was performed before and 1 week and 1 month after the B-RTO, and followed every 6 months thereafter. After baseline measurements, B-RTO was performed. Four weeks after the B-RTO, the same catheter measurements were repeated. RESULTS: The B-RTO was successful in all patients. Contrast-enhanced computed tomography showed complete obliteration of the SRS prior to the follow-up measurements. Endoscopic eradication of the fundal varices was obtained 6 months after B-RTO in all patients and encephalopathy was improved within 1 week after B-RTO. Following the B-RTO, hepatic blood flow (441 +/- 214 vs 668 +/- 299 mL/min, P < 0.0001) and the intrinsic clearance of ICG (233 +/- 123 vs 285 +/- 148 mL/min, P < 0.05) were significantly increased. Furthermore, intrahepatic resistance decreased after the B-RTO (P < 0.005). CONCLUSION: From short-term assessment, B-RTO increases hepatic blood flow and improves the metabolic activity of the liver in patients with portal hypertension.     

Detection of BCL2-IGH rearrangement on paraffin-embedded tissue sections obtained from a small submucosal tumor of the rectum in a patient with recurrent follicular lymphoma

A 59-year-old woman was admitted to our hospital because of recurrent follicular lymphorna (FL). Colonoscopic examination revealed a rectal submucosal tumor (SMT) without any erosions and ulcers. In this patient, it was difficult to distinguish non-Hodgkin‘s lymphoma (NHL) invasion from other disorders of the colon including carcinoid tumor merely based on endoscopic findings. Histopathologic and immunohistochemical studies on biopsy specimens showed an infiltration of atypical lymphocytes that were positive for CD20 and BCL2 but negative for UCHL-1. Fluorescence in situ hybridization on paraffin-embedded tissue sections (T-FISH) identified a translocation of BCL2 with IGHgene.Based on these findings, the tumor was defined as an invasion of FL. T-FISH method is useful for the detection of a monoclonality of atypical lymphocytes in an SMT of the gastrointestinal tract, and particularly for the detection of chromosomal translocations specific to lymphoma subtypes.     

Atorvastatin slows the progression of cardiac remodeling in mice with pressure overload and inhibits epidermal growth factor receptor activation.

The aim of this study was to investigate whether atorvastatin inhibits epidermal growth factor receptor (EGFR) activation in cardiomyocytes in vitro and slows the progression of cardiac remodeling induced by pressure overload in mice. Either atorvastatin (5 mg/kg/day) or vehicle was orally administered to male C57BL/6J mice with transverse aortic constriction (TAC). Physiological parameters were obtained by echocardiography or left ventricular (LV) catheterization, and morphological and molecular parameters of the heart were also examined. Furthermore, cultured neonatal rat cardiomyocytes were studied to clarify the underlying mechanisms. Four weeks after TAC, atorvastatin reduced the heart/body weight and lung/body weight ratios (8.69+/-0.38 to 6.45+/-0.31 mg/g (p<0.001) and 10.89+/-0.68 to 6.61+/-0.39 mg/g (p<0.01) in TAC mice with and without atorvastatin, respectively). Decrease of LV end-diastolic pressure and the time constant of relaxation, increased fractional shortening, downregulation of a disintegrin and metalloproteinase (ADAM)12, ADAM17 and heparin-binding epidermal growth factor genes, and reduction of the activity of EGFR and extracellular signal-regulated kinase (ERK) were observed in the atorvastatin group. Phenylephrine-induced protein synthesis, phosphorylation of EGFR, and activation of ERK in neonatal rat cardiomyocytes were all inhibited by atorvastatin. These findings indicated that atorvastatin ameliorates cardiac remodeling in mice with pressure overload, and its actions are associated with inhibition of the EGFR signaling pathway.     

Bone lesions in elderly multiple myeloma

We investigated the incidence of bone lesions in elderly cases of multiple myeloma (MM) and the course of those lesions, and also evaluated the relationships of skeletal symptoms with prognostic factors, and prognosis. The subjects were 146 patients, aged 65 years or more (median age 74, range 65-97 year), who were admitted to 11 institutions between January, 1988 and December, 1997. They consisted of 64 men and 82 women. The disease type was IgG type in 88 patients, IgA type in 37 patients, Bence-Jones (BJ) type in 17 patients, IgD type in three patients, and non-secretory type in one patient. Bone lesions in elderly MM patients were compared with those in 65 non-elderly MM patients. Skeletal symptoms were noted in 104 patients, and bone pain in 75 patients at the time of diagnosis. The bone lesions were evaluated as only osteolytic lesions in 26 patients, osteolytic lesions + osteoporosis in 23 patients, only osteoporosis in 2 patients and pathologic bone fractures in 53 patients. The occurrence rate of osteoporosis plus osteolytic lesion was higher in elderly patients (63.5%) than that in non-elderly patients (NE-MM group) (28.3%) (p < 0.0001). The bone lesions were most often observed in lumbar vertebrae (58.7%), cranial bone (56.7%), thoracic vertebrae (40.4%) and ribs (27.9%). The occurrence rate of bone lesion in lumbar vertebrae was higher in elderly patients (58.7%) than that in non-elderly patients (22.6%) (p < 0.0001). The life activities were limited in 71 patients because of the bone lesions. The relationship between the prognostic factors of MM and bone lesions was evaluated. There was a significant difference in the serum Ca level between patients with and without bone pain (P < 0.0001) and between those with and without pathologic bone fracture (P < 0.01). There was a significant difference in the appearance rate of plasma cells in the bone marrow between the patients with and without bone lesions (P < 0.05), between those with and without bone pain (P < 0.01), and between those with and without pathologic fracture (P < 0.05). There was a significant difference in the serum beta 2-microglobulin level between the patients with and without bone pain, and between those with and without pathologic fracture. There were no significant differences in survival times between elderly MM patients with and without bone lesions, bone pain and pathological bone fractures, while significant differences of survival times were found between non-elderly MM patients with and without bone lesions, bone pain and pathological bone fractures (P < 0.05, each). These data suggest that there are some differences in bone lesions between elderly and non-elderly MM patients.     

Protocol digest of randomized phase II study of modified FOLFIRINOX versus gemcitabine plus nab-paclitaxel combination therapy for locally advanced pancreatic cancer: Japan clinical oncology group study (JCOG1407)

Gemcitabine is one of the standard treatments for locally advanced pancreatic cancer. Recent studies on metastatic pancreatic cancer have shown that combination chemotherapy with oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel (GnP) prolonged the overall survival compared with gemcitabine alone. To select the most promising chemotherapy, a randomized phase II selection design trial was started in July 2016 to compare between modified FOLFIRINOX and GnP for patients with locally advanced pancreatic cancer. A total of 124 patients will be enrolled from 36 Japanese institutions within 2.5 years. The primary endpoint is the proportion of 1-year overall survival, and secondary endpoints are progression-free survival, distant metastasis-free survival, response rate in patients with target lesions, CA19-9 response, adverse events, treatment-related death, early death, grade 4 non-hematological toxicity, and dose intensity. This trial has been registered with the UMIN Clinical Trials Registry [http://www.umin.ac.jp/ctr/index.htm], and the registration number is UMIN000023143.     

Therapeutic Interventions for Increasing Ankle Dorsiflexion After Ankle Sprain: A Systematic Review

Context:

Clinicians perform therapeutic interventions, such as stretching, manual therapy, electrotherapy, ultrasound, and exercises, to increase ankle dorsiflexion. However, authors of previous studies have not determined which intervention or combination of interventions is most effective.

Objective:

To determine the magnitude of therapeutic intervention effects on and the most effective therapeutic interventions for restoring normal ankle dorsiflexion after ankle sprain.

Data Sources:

We performed a comprehensive literature search in Web of Science and EBSCO HOST from 1965 to May 29, 2011, with 19 search terms related to ankle sprain, dorsiflexion, and intervention and by cross-referencing pertinent articles.

Study Selection:

Eligible studies had to be written in English and include the means and standard deviations of both pretreatment and posttreatment in patients with acute, subacute, or chronic ankle sprains. Outcomes of interest included various joint mobilizations, stretching, local vibration, hyperbaric oxygen therapy, electrical stimulation, and mental-relaxation interventions.

Data Extraction:

We extracted data on dorsiflexion improvements among various therapeutic applications by calculating Cohen d effect sizes with associated 95% confidence intervals (CIs) and evaluated the methodologic quality using the Physiotherapy Evidence Database (PEDro) scale.

Data Synthesis:

In total, 9 studies (PEDro score = 5.22 ± 1.92) met the inclusion criteria. Static-stretching interventions with a home exercise program had the strongest effects on increasing dorsiflexion in patients 2 weeks after acute ankle sprains (Cohen d = 1.06; 95% CI = 0.12, 2.42). The range of effect sizes for movement with mobilization on ankle dorsiflexion among individuals with recurrent ankle sprains was small (Cohen d range = 0.14 to 0.39).

Conclusions:

Static-stretching intervention as a part of standardized care yielded the strongest effects on dorsiflexion after acute ankle sprains. The existing evidence suggests that clinicians need to consider what may be the limiting factor of ankle dorsiflexion to select the most appropriate treatments and interventions. Investigators should examine the relationship between improvements in dorsiflexion and patient progress using measures of patient self-reported functional outcome after therapeutic interventions to determine the most appropriate forms of therapeutic interventions to address ankle-dorsiflexion limitation.Key Words: chronic ankle instability, range of motion, stretching, joint mobilization

Key Points

• A static-stretching intervention as part of a standardized home exercise program had the strongest effects on ankle-dorsiflexion improvement after acute ankle sprains.
• Clinicians need to consider what may be the limiting factor of ankle dorsiflexion to select the most appropriate treatments and interventions.
• Investigators should examine the long-term effects of treatments on ankle dorsiflexion and a relationship between an improvement in ankle dorsiflexion and measures of patient self-reported and physical function to determine the most appropriate forms of therapeutic interventions to address limited dorsiflexion.

Lateral ankle sprain has been documented to be the most common lower extremity injury sustained during sport participation.^1–4 Approximately 85% of all ankle sprains result from an inversion mechanism and damage to the lateral ligamentous complex of the ankle.⁵ Injury to the lateral ligamentous complex at the ankle joint results in pain, swelling, and limited osteokinematics.⁶ A loss of normal ankle dorsiflexion usually is observed at the talocrural joint after lateral ankle sprain.^7–12The amount of available ankle dorsiflexion plays a key role in the cause of lower extremity injuries.^7,13–22 Limitation of dorsiflexion may be a predisposition to reinjury of the ankle^11,16 and several future lower limb injuries, including plantar fasciopathy,^13,20,21 lateral ankle sprains,^13,15,17,19 iliotibial band syndrome,¹⁴ patellofemoral pain syndrome,¹⁸ patellar tendinopathy,²² and medial tibial stress syndrome.¹⁴The importance of restoring ankle dorsiflexion after an acute ankle sprain often is emphasized in rehabilitation guidelines,⁹ and proper recovery of ankle dorsiflexion is a vital component of ankle rehabilitation. Inadequate restoration of ankle dorsiflexion may increase the risk of developing recurrent ankle sprain^11,16 and limit functional activities, such as walking, with long-term pain and disability.²³ Limited ankle-dorsiflexion range of motion (ROM) after lateral ankle sprain has been considered a predisposing factor for recurrent ankle sprain because diminished dorsiflexion prevents the ankle from reaching its closed-pack position by holding the ankle in a hypersupinated position. Therefore, ensuring appropriate restoration of ankle dorsiflexion after ankle sprain has important clinical implications for restoring full functional abilities, ultimately leading to reduced risk of recurrent ankle sprain.Clinicians perform several therapeutic interventions, such as stretching, manual therapy, electrotherapy, ultrasound, and exercises, to increase ankle dorsiflexion. However, the intervention or combination of interventions that most effectively improves ankle dorsiflexion has not been established. In previous systematic reviews,^24–26 researchers have examined the effects of specific intervention techniques of manipulative therapy on various outcome variables. In addition, Bleakley et al²⁷ conducted a systematic review with a comprehensive search of various therapeutic interventions to provide evidence for the management of ankle sprains and the prevention of long-term complications; however, the authors focused only on patients with an acute ankle sprain. Therefore, the purpose of this systematic review was to determine the magnitude of therapeutic intervention effects on and the most effective therapeutic interventions for restoring normal ankle dorsiflexion after ankle sprain. In contrast to previous reviews,^24–26 we comprehensively searched the existing literature to determine the effectiveness of various therapeutic intervention techniques in restoring ankle dorsiflexion in patients with acute, subacute, or recurrent ankle sprains. By providing a quantitative estimate of the magnitude of the effect of therapeutic interventions, our review provides a new perspective on the evidence of interventions to restore ankle dorsiflexion in various stages of ankle-sprain conditions.