Efficacy and safety of ustekinumab in Japanese patients with severe atopic dermatitis: a randomized, double-blind, placebo-controlled, phase II study.

BACKGROUND: Ustekinumab, a fully human monoclonal antibody against interleukin-12/23, may potentially be effective for severe atopic dermatitis (AD) treatment. OBJECTIVES: To evaluate efficacy and safety of ustekinumab 45 mg and 90 mg in patients with severe AD. METHODS: In this randomized, placebo-controlled, phase II study, Japanese patients (aged 20-65 years) with severe or very severe AD entered a 12-week double-blind treatment period during which they received (1 : 1 : 1) ustekinumab 45 mg, 90 mg or placebo subcutaneous injections at weeks 0 and 4, with follow-up until week 24. The primary efficacy end point was percentage change from baseline in Eczema Area and Severity Index (EASI) score at week 12. Major secondary efficacy end points included the proportion of patients achieving EASI 50, EASI 75, Investigator's Global Assessment score 0-1, change from baseline Atopic Dermatitis Itch Scale and Dermatology Life Quality Index. RESULTS: A total of 79 patients were randomized [ustekinumab 45 mg (n = 24), 90 mg (n = 28), placebo (n = 27)]. Ustekinumab treatment showed nonsignificant improvement in least square mean change from baseline EASI score at week 12 [45 mg: -38·2%, 95% confidence interval (CI) -21·02-19·51; P < 0·94 and 90 mg: -39·8%, 95% CI -21·84-17·14; P < 0·81] vs. placebo (-37·5%). A nonsignificant improvement in major secondary efficacy end points was observed in both ustekinumab groups vs. placebo. The most common treatment-emergent adverse events were nasopharyngitis and worsened AD (higher in placebo vs. ustekinumab groups). CONCLUSIONS: Ustekinumab 45 mg and 90 mg did not demonstrate meaningful efficacy in Japanese patients with severe AD. The treatment was generally well tolerated.

Reduced risk of hepatocellular carcinoma after interferon therapy in aged patients with chronic hepatitis C is limited to sustained virological responders.

This study was undertaken to investigate the effect of interferon (IFN) monotherapy on the risk of hepatocellular carcinoma (HCC) in aged-patients with chronic hepatitis C. Seven hundred and twenty-five patients with histologically proven chronic hepatitis C were enrolled in this retrospective cohort study; 531 received IFN monotherapy for 6 months between 1992 and 1995, and 157 were collected as a historical control. The effect of IFN therapy on the development of HCC was compared between the patients with chronic hepatitis C under 60 years old (non-aged group, n = 531) and those 60 and over (aged group, n = 194). A stepwise Cox proportional-hazards regression analysis in the non-aged group revealed that IFN therapy (risk ratio 0.52, 95% CI 0.33-0.81, P = 0.004), older age (P = 0.001), and higher histological stage (P < 0.001) were independent factors associated with the development of HCC. In the aged-group, only higher histological stage (P = 0.002) and male gender (P = 0.011), but not IFN therapy (risk ratio 0.77, 95% CI 0.42-1.40, P = 0.386), were identified as independent risk factors for HCC, although HCC was significantly reduced when sustained virological response (SVR) was obtained (risk ratio 0.23, 95% CI 0.08-0.64, P = 0.005). In conclusion, inhibitory effect of IFN on development of HCC in the patients with chronic hepatitis C aged 60 and over was limited to the patients achieving SVR when treated with 6 months-IFN monotherapy.

Ribavirin dose reduction raises relapse rate dose-dependently in genotype 1 patients with hepatitis C responding to pegylated interferon alpha-2b plus ribavirin.

The impact of ribavirin exposure on virologic relapse remains controversial in combination therapy with pegylated interferon (Peg-IFN) and ribavirin for patients with chronic hepatitis C (CH-C) genotype 1. The present study was conducted to investigate this. Nine hundred and eighty-four patients with CH-C genotype 1 were enrolled. The drug exposure of each medication was calculated by averaging the dose actually taken. For the 472 patients who were HCV RNA negative at week 24 and week 48, multivariate logistic regression analysis showed that the degree of fibrosis (P = 0.002), the timing of HCV RNA negativiation (P < 0.001) and the mean doses of ribavirin (P < 0.001) were significantly associated with relapse, but those of Peg-IFN were not. Stepwise reduction of the ribavirin dose was associated with a stepwise increase in relapse rate from 11% to 60%. For patients with complete early virologic response (c-EVR) defined as HCV RNA negativity at week 12, only 4% relapse was found in patients given > or = 12 mg/kg/day of ribavirin and ribavirin exposure affected the relapse even after treatment week 12, while Peg-IFN could be reduced to 0.6 microg/kg/week after week 12 without the increase of relapse rate. Ribavirin showed dose-dependent correlation with the relapse. Maintaining as high a ribavirin dose as possible (> or = 12 mg/kg/day) during the full treatment period can lead to suppression of the relapse in HCV genotype 1 patients responding to Peg-IFN alpha-2b plus ribavirin, especially in c-EVR patients.

Pegylated interferon alpha-2b (Peg-IFN alpha-2b) affects early virologic response dose-dependently in patients with chronic hepatitis C genotype 1 during treatment with Peg-IFN alpha-2b plus ribavirin.

Chronic hepatitis C (CH-C) genotype 1 patients who achieved early virologic response have a high probability of sustained virologic response (SVR) following pegylated interferon (Peg-IFN) plus ribavirin therapy. This study was conducted to evaluate how reducing drug doses affects complete early virologic response (c-EVR) defined as hepatitis C virus (HCV) RNA negativity at week 12. Nine hundred eighty-four patients with CH-C genotype 1 were enrolled. Drug doses were evaluated independently on a body weight base from doses actually taken. From multivariate analysis, the mean dose of Peg-IFN alpha-2b during the first 12 weeks was the independent factor for c-EVR (P = 0.02), not ribavirin. The c-EVR rate was 55% in patients receiving > or = 1.2 microg/kg/week of Peg-IFN, and declined to 38% at 0.9-1.2 microg/kg/week, and 22% in patients given <0.9 microg/kg/week (P < 0.0001). Even with stratified analysis according to ribavirin dose, the dose-dependent effect of Peg-IFN on c-EVR was observed, and similar c-EVR rates were obtained if the dose categories of Peg-IFN were the same. Furthermore, the mean dose of Peg-IFN during the first 12 weeks affected HCV RNA negativity at week 24 (P < 0.0001) and SVR (P < 0.0001) in a dose-dependent manner. Our results suggest that Peg-IFN was dose-dependently correlated with c-EVR, independently of ribavirin dose. Thus, maintaining the Peg-IFN dose as high as possible during the first 12 weeks can yield HCV RNA negativity and higher c-EVR rates, leading to better SVR rates in patients with CH-C genotype 1.

[Coronary malperfusion due to acute type A aortic dissection; surgical strategy and results].

Coronary malperfusion due to acute type A aortic dissection (DAA) is a lethal complication. It is especially difficult to rescue the patients with left coronary malperfusion because of acute global myocardial infarction (AMI), even with successful surgical treatments, including the replacement of the ascending aorta and coronary artery bypass grafting (CABG). We review our experience and illustrate our approach to these critically ill patients. In addition, we classify the mechanism of malperfusion into 4 types based upon perioperative findings and discuss surgical management indivisually. From January 1990 to April 2005, a total of 260 patients were operated for DAA in our institution. Twenty (7.7%) patients, 11 men and 9 women were suffering from coronary malperfusion due to DAA. The mean age was 55 (range 28-72) years. The right coronary artery was involved in 9 patients, and the left in 11. All procedures such as graft replacement and CABG were done on an emergent or urgent basis. Hospital mortality rate of right coronary malperfusion was 22% (2/9 patients), and that related to left coronary malperfusion was 5/11 (45%). Assisting device was required in 9 cases, veno-arterial bypass (VAB) in 6 cases, left ventricular assist system (LVAS) in 1, left heart bypass (LHB) in 1, LHB+right heart bypass (RHB) in 1. We lost all patients using VAB. Only 3 patients supported with strong assist device survived. Aggressive myocardial resuscitation and early operation are the key factors in the management of these critically ill patients. But once severe myocardial infarction occurs, V-A bypass (percutaneous cardiopulmonary support) is useless in treating patients with DAA who develop severe heart failure. We recommend to implant stronger assist device including LVAS immediately before exacerbation of multiple organ failure. In conclusion, surgical management is not easy for emergency patients with DAA in association with myocardial ischemia. However, reasonable surgical results can be obtained with supplemental CABG and strong mechanical support of the left ventricle.

Older Adults with Fear of Falling Show Deficits in Motor Imagery of Gait.

OBJECTIVE: Understanding of the underlying mechanisms of Fear of Falling (FoF) could help to expand potential treatments. Given the nature of motor performance, the decline in the planning stage of motor execution may be associated with an expression of FoF. The aim of this study was to assess the planning/prediction accuracy in motor execution in people with FoF using gait-related motor imagery (MI). DESIGN: Cross-sectional case/control study. SETTING: Three health centers in Japan. PARTICIPANTS: Two hundred and eighty-three community-dwelling older adults were recruited and stratified by presence of FoF as FoF group (n=178) or non-FoF group (n=107). MEASUREMENTS: Participants were tested for both imagery and execution tasks of a Timed Up and Go (TUG) test. The participants were first asked to imagine the trial (iTUG) and estimate the time it would take, and then perform the actual trial (aTUG). The difference between iTUG and aTUG (Δ TUG) was calculated. RESULTS: The FoF group was significantly slower in aTUG, but iTUG duration was almost identical between the two groups, resulting in significant overestimation in the FoF group. The adjusted logistic regression analysis showed that increased Δ TUG (i.e., tendency to overestimate) was significantly associated with FoF (OR = 1.05; 95% CI = 1.02-1.10). Low frequency of going outdoors was also associated with FoF (OR 2.95; 95% CI: 1.16-7.44). CONCLUSIONS: Older adults with FoF overestimate their TUG performance, reflecting impairment in motor planning. Overestimation of physical capabilities can be an additional explanation of the high risk of falls in this population.

[Aortic root remodeling and coronary artery bypass grafting for acute type A aortic dissection involving the left main coronary artery; report of a case].

A 56-year-old male was admitted for sudden chest pain followed by loss of consciousness and paraplegia. The electrocardiogram (ECG) revealed ST-elevation in leads II, III, and aVF and ST-depression in leads V3 to V6. The ultrasonic cardiography (UCG) demonstrated an intimal flap in the ascending aorta, grade III aortic regurgitation (AR), and akinesis of the posterior wall of the left ventricle. Transesophageal echocardiography directly showed dissection of the left main coronary artery. Emergency coronary artery bypass grafting (CABG) to the left anterior descending artery (LAD), obtuse marginal artery (OM) and posterolateral artery (PL) was performed using the saphenous vein. In addition, valve-sparing aortic root remodeling was performed in conjunction with replacement of the ascending aorta. The left coronary orifice was repaired and reattached to the prosthetic graft. The patient was weaned from cardiopulmonary bypass without catecholamine support. He was discharged from the hospital on foot after rehabilitation of the paraplegia. AR remains mild by UCG 3 years after surgery.

Truncation at the C-terminus of the DAX-1 protein impairs its biological actions in patients with X-linked adrenal hypoplasia congenita.

The DAX-1 [DSS (dosage-sensitive sex)-AHC critical region in the X, gene 1] gene has been reported to be responsible for X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism. However, the function and structure of the DAX-1 protein have not been characterized. In this study, molecular analysis of the DAX-1 gene from 6 patients with AHC, including 2 siblings, identified 5 novel mutations with 3 nonsense mutations and 2 frameshift mutations. Case 1 had a nonsense mutation at position 395 (Q395X). Cases 2 and 3, who were siblings, had a nonsense mutation at position 91 (Y91X). Case 4 had a 2-base deletion (AT) at nucleotides 1610 and 1611 and a 1-base insertion (G) resulting in a premature stop codon at position 462 (1610-1611 del AT ins G). Case 5 had a nonsense mutation at position 271 (Y271X). Case 6 had a 1-base deletion (C) at nucleotide 1169, which induced a frame shift and a premature stop codon at position 371 (1169 del C). All mutated DAX-1 proteins had truncated C-terminal domains. In addition, reverse transcription-PCR and direct sequencing characterized the mutant messenger ribonucleic acid in testis from case 1. Our results suggest that these 5 novel mutations are responsible for X-linked AHC and that the C-terminus of the DAX-1 protein, especially the terminal 11 amino acids, is necessary for normal adrenal cortical embryogenesis.

Reconsidering the 90 degrees head-rotation paradigm used in neuropsychological research: are there reflexive rather than hemispatial effects?

The 90 degrees head-rotation paradigm has often been used in neuropsychological studies to manipulate external hemispace (circumcorporeal space) relative to the head. Under the 90 degrees head-rotation paradigm, the performance of limb and hand movements carried out within the left or right hemispace as defined by head positions relative to the body is likely to be affected by the reflexive effect due to the neck and vestibular afferent inputs elicited by the head rotations, as well as by the hemispatial effect. Using the H-reflex technique, the present study examined whether the reflexive effect on the spinal motoneuron excitability occurred with head rotations under the 90 degrees head-rotation paradigm. The results showed that the amplitudes of H-reflexes evoked on both the thumb flexor and soleus muscles were not affected by head rotations, indicating no reflexive change in the spinal motoneuron excitability for both the thumb and soleus muscles. This finding suggests that the reflexive effect due to neck and vestibular afferent inputs can be ruled out from possible causal factors influencing the motor performance of limb and hand movements performed within the left or right hemispace as manipulated by the 90 degrees head-rotation paradigm.

Active specific immunotherapy using the immune reaction of a low-dose irradiated tumor tissue.

Active specific immunotherapy using the immune reaction of a low-dose irradiated tumor tissue was studied on the transplanted MM46 tumor of female C3H/He mice after radiotherapy. MM46 tumor cells were inoculated into the right hind paws of mice. On the 5th day, irradiation with the dose of 3000 rad was performed. On the 11th day, tumor cells and mononuclear cells, which were separated from the low-dose irradiated tumor tissue (2000 rad on the fifth day), were injected into the left hind paws of the tumor-bearing mice. Effectiveness of this active specific immunotherapy against tumor was evaluated by the regression of tumor and survival rate of mice. Tumor was markedly regressed and survival rate was significantly increased by the active specific immunotherapy.

Right ventricular thrombosis early after bidirectional Glenn shunt.

Thrombosis in the right ventricle occurred early after bidirectional superior cavopulmonary shunt in 2 patients with pulmonary atresia with intact ventricular septum and major right ventricular coronary artery communication, and perioperative brain infarction occurred in 1 patient. Clinicians should be aware of the hazards of this potentially lethal complication, and transfusion of platelets and fresh plasma should be minimized. Although the hemodynamic state is good, echocardiography should be performed frequently and strict anticoagulation should be started as early as possible.

Hemodynamic effects of carbon dioxide insufflation under single-lung ventilation during thoracoscopy.

BACKGROUND: The hemodynamic effects of carbon dioxide insufflation under single-lung ventilation were studied in 22 consecutive thoracoscopic harvests of the left internal mammary artery, which was used for minimally invasive coronary artery bypass grafting. METHODS: An electrocardiograph, arterial catheter, Swan-Ganz catheter, and transesophageal echocardiograph were used to monitor seven hemodynamic variables. Baseline data were obtained during ventilation of both lungs and the measurements were repeated after the left lung was collapsed and at 5 and 30 minutes after hemithorax insufflation with low-flow (2 to 3 L/minute) carbon dioxide gas was begun. The intrapleural pressure was maintained at 8 to 10 mm Hg. RESULTS: Thoracoscopic harvest of the internal mammary artery was completed in all cases with a mean insufflation time of 44+/-12 minutes. There were no significant changes in the mean arterial pressure, heart rate, cardiac index, and left ventricular ejection fraction throughout the procedure, whereas the central venous pressure, mean pulmonary arterial pressure, and pulmonary capillary wedge pressure (p < 0.05 for each variable) during insufflation. CONCLUSIONS: Low-flow carbon dioxide insufflation into the left hemithorax with an intrapleural pressure of 8 to 10 mm Hg under selective right-lung ventilation does not compromise the human heart with normal to moderately depressed function and can be an efficacious adjunct in specific thoracoscopic procedures.

Unilateral absence of pulmonary artery and ventricular septal defect in an infant.

A 2-month-old boy was diagnosed as having a rare combination of absence of left pulmonary artery and ventricular septal defect. He underwent intracardiac repair at the age of 8 months. Reconstruction of the left pulmonary artery was impossible because it could not be visualized through a median sternotomy. Although his early postoperative course was uneventful, he needed ipsilateral pneumonectomy 3 months later because of unremitting hemoptysis. Hilar left pulmonary artery, which used to exist, was not found even by histologic examination.

Evident difference in the excitability of the motoneuron pool between normal subjects and patients with spasticity assessed by a new method using H-reflex and M-response.

The excitability of the motoneuron (MN) pool in the resting state was compared between normal control subjects and patients with spasticity resulting from HTLV-I-associated myelopathy, using a new parameter, Hslp/Mslp, and the conventional parameters Hmax/Mmax and Hth/Mth. Differences in the excitability of the MN pool between these two groups reached a high degree of statistical significance only when assessed with the new parameter. This suggests the methodological advantage of the Hslp/Mslp over both Hmax/Mmax and Hth/Mth for evaluation of the excitability of the MN pool in the resting state.

L-Arginine given after ischaemic preconditioning can enhance cardioprotection in isolated rat hearts.

OBJECTIVE: Ischaemic or pharmacological preconditioning with L-arginine has been reported to be insufficient for optimal cardioprotection. The ability of nitric oxide (NO) to enhance ischaemic preconditioning was assessed, and the role of L-arginine-induced ischaemic preconditioning in myocardial protection was determined. METHODS: Isolated rat hearts were prepared and divided into six groups: control hearts (control, n=6) were perfused without global ischaemia at 37 degrees C for 160 min; global ischaemia hearts (GI, n=6) were subjected to ischaemia for 20 min and reperfusion for 120 min; ischaemic preconditioned hearts (IP, n=6) received 2 min of zero-flow global ischaemia followed by 5 min reperfusion, before 20 min of global ischaemia; L-arginine hearts (ARG, n=6) received 1 mmol/l L-arginine for 5 min, before 20 min of global ischaemia; ischaemic preconditioning plus nitro-L-arginine methyl ester hearts (IP+L-NAME, n=6) received 2 min of ischaemic preconditioning and 5 min reperfusion with 3 mmol/l L-NAME in Krebs-Henseleit buffer, before 20 min of global ischaemia; and ischaemic preconditioning plus L-arginine hearts (IP+ARG, n=6) received 2 min of ischaemic preconditioning and 5 min reperfusion with 1 mmol/l L-arginine in Krebs-Henseleit buffer. Haemodynamic parameters and coronary flow were recorded continuously. Nitrites and nitrates (NOx) were measured 5 and 60 min after reperfusion, and infarct size was also determined. RESULTS: In the IP+ARG group, significant amelioration and preservation of left ventricular peak developed pressure and coronary flow was observed compared with the GI, IP, ARG and IP+L-NAME groups. Infarct size in the IP+ARG group was reduced significantly compared with that in the GI, IP, ARG and IP+L-NAME groups. Significant preservation of NOx was observed during reperfusion in the IP+ARG group compared with the GI group. CONCLUSIONS: Inhibition of NO synthase with L-NAME had little impact on ischaemic preconditioning, suggesting that endogenous NO is not a major mediator of ischaemic preconditioning. Nevertheless, enhancement of the effects of ischaemic preconditioning can be achieved with L-arginine, a precursor of NO, improving post-ischaemic functional recovery and infarct size in the isolated rat heart.

One-stage total repair of severe hypospadias with scrotal transposition: experience in 18 cases.

This is a report detailing further experience with our one-stage repair of severe hypospadias and scrotal transposition performed on 18 patients. Initial success was obtained in 12 cases, while two more were improved by secondary repair. The operative technique, as modified, assures a parameatal preputial flap, which is well vascularized and easily constructed into a neourethra. The advantages of this improved "glanulomeatoplasty" and scrotoplasty are discussed. The method is recommended as an excellent functional and cosmetic procedure for one-stage correction of severe hypospadias.

Myocardial ultrastructure in Kearns-Sayre syndrome.

Myocardial ultrastructural changes are described in a twenty-five-year-old female with typical Kearns-Sayre syndrome. The electrocardiogram revealed complete atrioventricular block with an occasional torsades de pointes type of ventricular tachycardia. His bundle recording demonstrated HV block with normal AH interval. An endomyocardial biopsy showed "ragged-red fibers" by the modified Gomori trichrome stain, and on electron microscopy there were increased numbers of morphologically abnormal mitochondria: ie, gian mitochondria, a whorled pattern of the cristae, and electron-dense substances, and paracrystalline inclusions in the mitochondria. The patient has been well since pacemaker implantation, but she may develop a clinically overt cardiomyopathy due to progression of myocardial involvement.

Memory for constrained and preselected movement location and distance.

These experiments assessed the interrelationship between location and distance cues in the coding of movements. In separate experiments subjects recalled either the terminal location or the distance of constrained (Experiment 1) or preselected (Experiment 2) movements following a 15-sec retention interval. Changes in direction amd amplitude of starting position were used to ascertain whether recall errors were related to these changes. The findings of both experiments indicated that location and distance were recalled with similar accuracy when the starting position was identical for the criterion and recall movement. However, analysis of constant errors when the recall starting position was varied in either direction clearly indicated neither terminal location nor distance are coded independently, and memory for movement is based on an interaction between these cues.

Favorable results in patients with small size CarboMedics heart valves in the aortic position.

Hemodynamic performance of the CarboMedics heart valve in the aortic position and its clinical impacts were investigated in 126 consecutive patients. The actuarial survival rates of patients who had undergone isolated aortic valve replacement and concomitant aortic and mitral valve replacement were 82.6+/-5.7% and 71.0+/-9.2% at 8 years, respectively. Morbid events were rare, and almost all late survivors were free from evident cardiac symptoms regardless of the valve size. Echocardiography revealed suboptimal transvalvular pressure gradients and effective orifice areas of 19 mm and 21 mm valves. However, relief of the left ventricular overload and improvement of the clinical symptoms as well as cardiac function were comparable to those of patients with larger valves. Valve function measured by echocardiography did not show significant correlation to late outcome. Good results can be expected even in the presence of echocardiographic data such as peak pressure gradient over 40 mmHg, effective orifice area less than 1.0 cm(2), and effective orifice area index less than 0.7 cm(2)/m(2).

Effects of recombinant human erythropoietin therapy on blood coagulation and fibrinolysis system.

This study was designed to examine the effects of recombinant human erythropoietin (rHuEPO) therapy on blood coagulation and fibrinolysis in patients scheduled for elective heart surgery and undergoing preoperative autologous blood donation. Twenty-seven patients were studied, of whom 16 patients received rHuEPO (group E) and 11 patients no rHuEPO therapy (group N). The patients in group E were given 6000 units of rHuEPO intravenously every other day, three times a week, beginning from two weeks prior to the operation. In both groups, 400 ml of blood was collected preoperatively for predeposit once a week for two weeks, and the self-donated blood was returned to the patient intra- and postoperatively. Blood samples were drawn at the beginning of the study, immediately before the operation and two weeks after the operation. They were analyzed to assess blood coagulation, fibrinolysis, platelet function and vascular endothelial cell function, in order to examine the effects of the administration of rHuEPO. No significant difference was observed between the two groups in the degree of changes in these parameters following the operation. As enhancement of blood coagulability and fibrinolytic activity was evident postoperatively in both groups, changes in these parameters during the preoperative autologous blood donation period were also assessed excluding the postoperative data. Again, there was no significant intergroup difference in any of the markers evaluated. It was concluded that the administration of rHuEPO during preoperative autologous blood donation is unlikely to affect coagulation and fibrinolysis.