Contributors of characteristic mitral flow velocity pattern in congestive heart failure--from clinical observations back to experimental validations.

Mitral flow velocity pattern in patients with left ventricular (LV) diastolic dysfunction usually includes decreased peak early diastolic filling velocity (E), slowed deceleration of the early diastolic filling wave and increased peak filling velocity at atrial contraction (A). However, the abnormal mitral flow velocity pattern can be normalized in the presence of concomitant congestive heart failure. In such cases E can be equal to or even higher than normal, its deceleration is normal or faster than normal value, and A can be normal or lower than normal value. Clinical observations in patients with severe heart failure showed that the mitral flow velocity pattern changes with vasodilating therapy, reflecting the changes in the left atrial (LA) to LV pressure difference rather than those in the absolute LA pressure or LV pressure alone. This was validated in the canine study in which levels of LV dysfunction were made by the injection of microspheres into the left coronary artery to study the interrelation among the mitral flow velocity pattern and LA and LV pressures. In this experiment, the changes in the mitral flow velocity pattern could not be explained by the changes in LA or LV pressure alone but was better explained by the changes in the LA to LV pressure difference. Not only LA-LV crossover pressure but also LA compliance seem to be important as determinants of LA pressure level in diastole. In addition to LV relaxation rate, incompleteness of relaxation, elastic recoil and LV passive elastic properties, extracardiac constraint is also considered to be an important determinant of the level of the LV diastolic pressure and hence of the mitral flow velocity pattern at least in the presence of congestive heart failure. Thus, mitral flow velocity pattern is determined by the interaction of LA and LV pressures, both of which are affected by chamber properties as well as loading conditions.     

Renal cell carcinoma with unusual metastasis to the gallbladder

Gallbladder involvement in patients with renal cell carcinoma (RCC) is extremely rare. We present a report of a 61-year-old man with a synchronous RCC metastasis to the gallbladder presenting as an intraluminal polypoid mass simulating primary gallbladder carcinoma. Enhanced abdominal computed tomography demonstrated a well-enhanced polypoid lesion in the gallbladder. Intraoperative rapid pathological examination of the gallbladder tumor showed clear cell-type cancerous cells. Microscopically, tumor cells of both the resected kidney and gallbladder had round uniform nuclei, clear cytoplasm, and well-defined cytoplasmic borders, forming alveolar patterns. Immunohistochemically, the tumor cells were negative for cytokeratin 7 (CK7) and carcinoembryonic antigen (CEA), which is usually positive in primary clear cell carcinoma of the gallbladder. Therefore, the final diagnosis was RCC with a synchronous gallbladder metastasis.     

The Japanese respiratory society guidelines for the management of cough and sputum (digest edition)

Cough and sputum are common complaints at outpatient visits. In this digest version, we provide a general overview of these two symptoms and discuss the management of acute (up to three weeks) and prolonged/chronic cough (longer than three weeks). Flowcharts are provided, along with a step-by-step explanation of their diagnosis and management. Most cases of acute cough are due to an infection. In chronic respiratory illness, a cough could be a symptom of a respiratory infection such as pulmonary tuberculosis, malignancy such as a pulmonary tumor, asthma, chronic obstructive pulmonary disease, chronic bronchitis, bronchiectasis, drug-induced lung injury, heart failure, nasal sinus disease, sinobronchial syndrome, eosinophilic sinusitis, cough variant asthma (CVA), atopic cough, chronic laryngeal allergy, gastroesophageal reflux (GER), and post-infectious cough. Antibiotics should not be prescribed for over-peak cough but can be considered for atypical infections. The exploration of a single/major cause is recommended for persistent/chronic cough. When sputum is present, a sputum smear/culture (general bacteria, mycobacteria), cytology, cell differentiation, chest computed tomography (CT), and sinus X-ray or CT should be performed. There are two types of rhinosinusitis. Conventional sinusitis and eosinophilic rhinosinusitis present primarily with neutrophilic inflammation and eosinophilic inflammation, respectively. The most common causes of dry cough include CVA, atopic cough/laryngeal allergy (chronic), GER, and post-infectious cough. In the last chapter, future challenges and perspectives are discussed. We hope that the clarification of the pathology of cough hypersensitivity syndrome will lead to further development of “pathology-specific non-specific therapeutic drugs” and provide benefits to patients with chronic refractory cough.     

Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial

OBJECTIVE: Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL-6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL-6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti-IL-6 receptor antibody, MRA, in patients with RA. METHODS: In a multicenter, double-blind, placebo-controlled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria. RESULTS: Treatment with MRA reduced disease activity in a dose-dependent manner. At 3 months, 78% of patients in the 8-mg group, 57% in the 4-mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8-mg group versus placebo). Forty percent of patients in the 8-mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4-mg, and 8-mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti-DNA antibodies. Anti-MRA antibodies were detected in 2 patients. CONCLUSION: Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.     

The role of subchondral insufficiency fracture in rapid destruction of the hip joint: a preliminary report

OBJECTIVE: The pathophysiology of rapidly destructive arthrosis of the hip joint (RDA) is unknown. The purpose of this study was to document cases of subchondral insufficiency fracture of the femoral head, which has similar clinicoradiologic features to those of early-stage RDA. METHODS: This study was based on a retrospective review of 11 cases of subchondral insufficiency fracture of the femoral head that were confirmed histopathologically and for which radiographs both at the onset of hip pain and at the time of surgery were available. RESULTS: All patients were > 60 years of age (range 61-78 years, mean age 69), and 9 were women. On plain radiographs, the normal joint space had undergone rapid narrowing and/or disappeared within 9 months (mean 5.8 months). Magnetic resonance imaging, available in 2 cases, showed a pattern of bone marrow edema from the upper portion of the femoral head to the intertrochanteric region, with an associated focal low-intensity band on T1 paralleling the articular surface. In all cases, evidence of subchondral insufficiency fracture was confirmed histopathologically. In addition, in the marrow space, there were several round-to-oval granulomatous foci, which consisted of amorphous debris, fragmented bone, and articular cartilage surrounded by reactive histiocytes and giant cells. All 11 patients were osteopenic, as shown both radiologically and histopathologically. CONCLUSION: Subchondral insufficiency fracture resulting from osteopenia may lead to a rapid breakdown of the hip joint.     

Modulation by thymus-derived (T) cells of thyroid cell-stimulated prostaglandin E release by human peripheral blood mononuclear cells.

Cultures of plastic-adherent, human peripheral blood mononuclear cells generated prostaglandin E (PGE). Culture of the adherent cells (predominantly monocytes) with human thyroid cells enhanced PGE accumulation in the medium, although to a lesser degree than occurs with unseparated blood mononuclear cells. Recombination of the adherent cells with monocyte-depleted, nonadherent cells restored both basal and thyroid cell-stimulated PGE generation to the levels seen with unseparated cells. Thymus-derived (T) cells, obtained by rosetting with sheep erythrocytes, similarly enhanced both the adherent cell basal PGE production as well as the increased PGE accumulation that occurs in the presence of thyroid cells (50-120% augmentation by the T cells). Significant augmentation of thyroid cell-stimulated PGE release by 10(5) adherent cells occurred with the addition of as few as 5 x 10(4) T cells. Culture medium transfer experiments and separation of cell types during culture by a semipermeable membrane provided evidence against the possibility that the adherent cells were releasing a factor that stimulated T-cell PGE generation or that T cells were releasing a factor that enhanced adherent cell PGE generation. The results suggest instead that this T-cell effect requires direct contact with the adherent cells. These data demonstrate the importance of human T cells in the release by adherent cells of PGE, a mediator of suppressor function by some immune cells.     

Isolation of transforming sequences of two human lung carcinomas: structural and functional analysis of the activated c-K-ras oncogenes.

Human lung tumors PR310 and PR371 maintained in nude mice contain activated c-K-ras oncogenes detectable by the ability of their DNAs to induce the morphological transformation of NIH 3T3 mouse fibroblasts. Using phage libraries constructed with DNA from NIH 3T3 mouse fibroblast transformants, we have isolated human sequences that span greater than 40 kilobase pairs of the c-K-ras oncogene. Based on the conservation of these human sequences in mouse fibroblast transformants, we conclude that the transforming ability of the oncogene activated in these tumors resides within a 43- to 46-kilobase-pair DNA region. No clear differences were observed between the structures of the PR310 and PR371 cloned oncogene sequences. Nucleotide sequence analysis in concert with DNA transfection experiments suggests that the PR371 oncogene has been activated by a single base change in the first exon, which results in the substitution of cysteine for glycine in position 12 of the predicted amino acid sequence. The genetic alteration responsible for the transforming activity of the PR310 oncogene, however, does not reside in the first exon. These results indicate that the activation of the c-K-ras oncogene in human lung cancer can occur by different mutational events.     

An L-selectin ligand distinct from P-selectin glycoprotein ligand-1 is expressed on endothelial cells and promotes neutrophil rolling in inflammation

Neutrophils recruited from the blood are key players in the innate immune response. Selectins play critical roles in neutrophil recruitment by mediating their tethering and rolling in inflamed venules. While the roles of P- and E-selectin in this process are well established, the mechanisms of L-selectin-mediated neutrophil recruitment remain elusive. One proposal is that tethering is mediated by L-selectin on flowing neutrophils interacting with P-selectin glycoprotein ligand-1 (PSGL-1) on adherent neutrophils. To clarify whether L-selectin-mediated neutrophil recruitment depends entirely on PSGL-1, we examined the impact of L-selectin deficiency in mice with a PSGL-1-deficient background. L-selectin and PSGL-1 double-knockout mice exhibited a higher increase in their peripheral blood neutrophil count and a worse defect in neutrophil recruitment into the inflamed peritoneum than PSGL-1-deficient mice. Intravital microscopy of inflamed cremaster muscle venules showed that L-selectindeficiency or antibody blockade of L-selectin reduced the residual leukocyte rolling in PSGL-1-deficient mice. Flow cytometric analyses showed that the endothelial cells from the cremaster muscle bound L-selectin in a PSGL-1-independent manner. These results provide evidence for the existence of an L-selectin ligand distinct from PSGL-1 in inflammation and indicate that such a ligand is expressed on endothelial cells, promoting neutrophil rolling in vivo.