Potent and specific antitumor effect of CEA‐targeted photoimmunotherapy

Conventional photodynamic therapy (PDT) for cancer is limited by the insufficient efficacy and specificity of photosensitizers. We herein describe a highly effective and selective tumor‐targeted PDT using a near‐infrared (NIR) photosensitizer, IRDye700DX, conjugated to a human monoclonal antibody (Ab) specific for carcinoembryonic antigen (CEA). The antitumor effects of this Ab‐assisted PDT, called photoimmunotherapy (PIT), were investigated in vitro and in vivo. The Ab‐IRDye conjugate induced potent cytotoxicity against CEA‐positive tumor cells after NIR‐irradiation, whereas CEA‐negative cells were not affected at all, even in the presence of excess photoimmunoconjugate. We found an equivalent phototoxicity and a predominant plasma membrane localization of Ab‐IRDye after both one and six hours of incubation. Either no or little caspase activation and membrane peroxidation were observed in PIT‐treated cells and a panel of scavengers for reactive oxygen species showed only partial inhibition of the phototoxic effect. Strikingly, Ab‐IRDye retained significant phototoxicity even under hypoxia. We established a xenograft model, which allowed us to sensitively investigate the therapeutic efficacy of PIT by non‐invasive bioluminescence imaging. Luciferase‐expressing MKN‐45‐luc human gastric carcinoma cells were subcutaneously implanted into both flanks of nude mice. NIR‐irradiation was performed for only the tumor on one side. In vivo imaging and measurement of the tumor size revealed that a single PIT treatment, with intraperitoneal administration of Ab‐IRDye and subsequent NIR‐irradiation, caused rapid cell death and significant inhibition of tumor growth, but only on the irradiated side. Together, these data suggest that Ab‐IRDye‐mediated PIT has great potential as an anticancer therapeutics targeting CEA‐positive tumors.     

A case of small cell lung carcinoma complicated by Lambert-Eaton myasthenic syndrome]

A 54-year old man was admitted with general fatigue, muscle weakness and dyspnea on effort. Medical examinations led to a diagnosis of small cell lung carcinoma (SCLC) with Lambert-Eaton myasthenic syndrome (LEMS). Marked improvement of SCLC and symptoms of LEMS were recognized twice during chemoradiotherapy. On his third admission, he showed muscle weakness, dysaethesia, and neurodysfunction of the bladder and rectum. We initially considered these symptoms to be due to spinal metastasis because MRI findings showed multiple spinal metastases. However, electoromyogram and nerve conduction study demonstrated that his muscle weakness resulted from LEMS though dysethesia and neurodysfunction of bladder and rectum were caused by spinal metastasis. We believe that it is important to perform electomyogram and nerve conduction studies, not only radiographic findings, to detect the "hidden" symptoms of LEMS.     

A case of anaphylactoid purpura associated with nephrosis followed by pulmonary tuberculosis

A 54-year old man was admitted to our hospital because of high fever, productive cough and purpura in both legs in June 2005. Urinalysis showed microscopic hematuria and proteinuria. Chest radiograph showed consolidation of right upper field. Because acid-fast bacilli and polymerase chain reaction test for Mycobacterium tuberculosis were positive in bronchial lavage fluid, we made a diagnosis of pulmonary tuberculosis, and prescribed antituberculosis therapy with isoniazid, rifampicin, ethambutol and pyrazinamide. In addition, anaphylactoid purpura was diagnosed by skin biopsy. In July 2005, renal function was deteriorated and nephrosis appeared. We treated with corticosteroid in addition to antituberculosis therapy. His symptoms and renal dysfunction improved. We report a rare case of an anaphylactoid purpura following occurence of pulmonary tuberculosis.     

Plasma atrial natriuretic peptide concentration inversely correlates with left atrial collagen volume fraction in patients with atrial fibrillation: plasma ANP as a possible biochemical marker to predict the outcome of the maze procedure.

OBJECTIVES: We hypothesized that the plasma atrial natriuretic peptide (ANP) level reflects atrial degenerative change and may predict the outcome of the maze procedure. BACKGROUND: Although a larger preoperative left atrial dimension and longer duration of atrial fibrillation (AF) have been reported in patients with persistent AF than in those with sinus rhythm (SR), these individual factors were not enough to predict the outcome of the maze procedure. METHODS: Preoperative plasma ANP levels were measured in consecutive 62 patients who underwent the Kosakai's modified maze procedure. Moreover, we performed histological and molecular biological examinations in the resected left atrial tissues. RESULTS: The preoperative plasma ANP was lower in the AF group (n = 13) than it was in the SR group (n = 49) (p < 0.001). Multiple logistic regression analysis revealed that duration of AF and plasma ANP were independently associated with postoperative cardiac rhythm. Among 41 patients with a higher plasma ANP or shorter duration of AF than the median value, SR was restored in 95% of patients. In contrast, in 21 patients with a lower plasma ANP and a longer duration of AF than the median value, SR was restored only in 48% of patients. Histological examination revealed that the collagen volume in the left atrial tissue was higher in AF than it was in SR and inversely correlated with plasma ANP. In addition, the messenger RNA expressions of ANP, collagen type I and type III were lower in AF than they were in SR. CONCLUSIONS: These results suggest that a combination of plasma ANP and/or duration of AF may predict the success rate for the maze operation. Advanced atrial degenerative change may result in a decrease of atrial ANP secretion.     

Perforin defects of primary haemophagocytic lymphohistiocytosis in Japan

The perforin gene was analysed in 15 Japanese patients with primary haemophagocytic lymphohistiocytosis (HLH). Perforin gene defects were found in two out of eight patients with familial HLH (FHL), and one out of seven without affected siblings. Four novel mutations were identified. Compound heterozygous mutations (one FHL and one sporadic HLH) and only one allele mutation (one FHL) were defined. Flow cytometry revealed no perforin expression in CD8+ or CD56+ cells from a surviving patient with a mutation. The frequency of mutation was at least 20% of FHL in Japan. Flow cytometry for intracellular perforin may be useful for the screening of FHL2.     

Hyperkinesis without the Frank-Starling mechanism in a nonischemic region of acutely ischemic excised canine heart

To determine the essential mechanism of increased systolic wall motion, i.e., hyperkinesis, in a nonischemic region (NIR) during acute ischemia, we simultaneously evaluated global and regional function of the excised, cross-circulated canine left ventricle connected to a volume servo pump before and after coronary occlusion. Regional areas were determined with pairs of orthogonal subendocardial sonomicrometers in the ischemic region (IR) and NIR. After coronary occlusion with left ventricular end-diastolic and stroke volumes kept constant, the amount of systolic area shrinkage (delta A) in NIR increased by 33 +/- 41% (p less than .05), despite a decrease in end-diastolic regional area by 3 +/- 4% (p less than .05). Regional work obtained from the wall tension-regional area (T-A) loop in NIR decreased by 50 +/- 24% due to a similar decrease in afterload despite the presence of hyperkinesis, indicating regional systolic unloading. When left ventricular end-diastolic volume was subsequently increased with a constant stroke volume, delta A in NIR increased at the expense of a further decrease in delta A in IR. The end-systolic T-A relationship in NIR remained unchanged, whereas that in IR markedly shifted rightward, suggesting that the contractile state of NIR was constant. These results indicate that hyperkinesis in NIR during acute ischemia can occur without a utilization of the Frank-Starling mechanism or an enhancement of regional contractile state, and that the essential mechanism of this phenomenon is regional afterload reduction due to an intraventricular mechanical interaction between IR and NIR.     

Endoscopic pancreatic sphincter balloon dilation for effective retrieval of pancreatic duct stone

To facilitate pancreatic stone retrieval, four patients with chronic pancreatitis and pancreatic stones underwent endoscopic pancreatic sphincter balloon dilation (EPSBD) rather than pancreatic sphincterotomy. Extracorporeal shock wave lithotripsy combined with endoscopic removal was carried out in three patients. Stone removal following EPSBD was completely successful in all four patients. Patients showed no severe complications during the dilation procedure. In one patient, to prevent pancreatitis, an endoscopic nasopancreatic drain was placed for 1 week after EPSBD. Compared with pancreatic sphincterotomy, EPSBD can be performed safely in patients with chronic pancreatitis to assist in the extraction of pancreatic duct stones. Use of the EPSBD procedure in cases of chronic pancreatitis provides a useful approach to improve endoscopic clearance of pancreatic duct stones.     

Mechanical efficiency of the left ventricle as a function of preload,afterload, and contractility

Summary We have recently shown that the mechanical efficiency of the contractile machinery of the canine left ventricle is constant at 30%–50%, independent of its loading, heart rate, and inotropic conditions. In contrast, the conventional mechanical efficiency of the ventricle is known to vary between 0 and 30%, depending on these conditions. In this study, we derived an equation for the conventional mechanical efficiency as a function of ventricular preload, afterload, and contractility, based on the constant mechanical efficiency of the contractile machinery. In deriving this equation, we fully utilized our new concept of the total mechanical energy of the left ventricle, i.e., systolic pressure-volume area, and our recent findings of the linear relationship between left ventricular oxygen consumption and the systolic pressure-volume area as well as the dependence of this relation on the ventricular inotropic state. As a result, the conventional mechanical efficiency of the left ventricle was found to change between 0 and 25% as an explicit function of these cardiodynamic and inotropic conditions. Using this function, we obtained combinations of loading and inotropic conditions to maximize the conventional mechanical efficiency of the left ventricle.     

Detection of IgM, IgA, and IgG antibodies to preS2 antigen in hepatitis B virus infection.

Antibodies to the preS2 antigen (anti-preS2) of the hepatitis B virus (HBV), including IgA, IgM and IgG classes, were observed in patients with acute and persistent HBV infection. In acute HBV infection, rapid and marked serum IgM and IgA anti-preS2 responses were observed. Antibodies reached a peak of serum activity at about 1-2 months after the onset of clinical symptoms, and both antibodies disappeared from serum at 4 months after. IgG anti-preS2 was detected in the early phase of the illness, then the level of IgG anti-preS2 gradually rose during the recovery phase. In persistent HBV infection, IgG and IgM anti-preS2 were detected in sera where the preS2 antigen was present, and IgM anti-preS2 was significantly higher (p less than 0.05) in HBeAg-positive than in HBeAg-negative patients. These results indicate that an adequate humoral immune response to the preS2 antigen is induced during acute and persistent HBV infection.