Effect of topical capsaicin on the cutaneous responses to inflammatory mediators and to antigen in man

Topical capsaicin pretreatment is known to deplete cutaneous sensory nerves of neuropeptides. We have assessed the effect of topical capsaicin pretreatment on the responses to intradermal injections of histamine and platelet-activating factor (PAF) in six normal subjects, and of prostaglandin E2, histamine, and antigen in 10 atopic subjects. Capsaicin pretreatment caused significant inhibition of the immediate flare response to histamine in both normal (19.8 +/- 2.6 to 7.3 +/- 2.9 cm2 at 5 minutes; p less than 0.01) and atopic subjects (16.5 +/- 1.4 to 10.3 +/- 1.9 cm2 at 5 minutes; p less than 0.01). The PAF-induced flare was also inhibited from 12.2 +/- 2.9 to 2.7 +/- 1.6 cm2 at 5 minutes after injection (p less than 0.01). In contrast, capsaicin pretreatment did not significantly alter the flare responses to prostaglandin E2 or antigen in atopic subjects. The acute wheal responses to all stimuli were unchanged, as was the late-phase response to antigen. These results support the hypothesis that the cutaneous vasodilator effect of histamine and PAF may be mediated by a local axon reflex involving the release of neuropeptides from sensory nerves. A consistent effect of capsaicin pretreatment on the flare response induced by endogenous mediators released during a cutaneous IgE-mediated response was not observed. Increases in microvascular permeability and the late-phase response to antigen are independent of neuropeptide release from cutaneous nerves.     

Sepsis-induced SOCS-3 expression is immunologically restricted to phagocytes

We have shown that immune cells from septic mice exhibit a suppressed response to exogenous stimuli in vitro. The suppressors of the cytokine signaling (SOCS) family are proteins that block intracellular signaling and can be induced by inflammatory mediators. Therefore, we hypothesized that SOCS-3 is up-regulated in immune cells in response to a septic challenge induced by cecal ligation and puncture (CLP). Mice were subjected to CLP or sham-CLP, and 2-48 h later, the blood, thymus, spleen, lung, and peritoneal leukocytes were harvested and examined. SOCS-3 was undetectable in thymocytes or blood leukocytes. In contrast, SOCS-3 was up-regulated in the spleen, lung, and peritoneal leukocytes in a time-dependent manner. Further examination revealed that only the macrophages and neutrophils expressed SOCS-3. These data suggest that cytokines and bacterial toxins present during sepsis have the ability to suppress the cytokine and/or lipopolysaccharide response and the function of immune cells by up-regulating SOCS-3.     

Altered patterns of migration of cytokine-producing T lymphocytes in skin-grafted naive or immune mice following in vivo administration of anti-VCAM-1 or -ICAM-1.

Naive or preimmunized (to B10.BR or BALB.k) C3H/HeJ mice received skin grafts from multiple minor histoincompatible B10.BR or BALB.k mice following antigen-specific portal venous (p.v.) pretransplant transfusion, a protocol known to produce prolongation of graft survival in naive animals. In addition, groups of mice received intravenous (i.v.) infusion following transplantation with a mixture of monoclonal antibodies (mAb) to vascular adhesion molecule-1L: very late activation antigen-4 (VCAM-1:VLA-4) or intracellular adhesion molecule-1:lymphocyte function-associated antigen-3 (ICAM-1:LFA-1). Cells were harvested from different tissues of the grafted mice at various times post grafting. RNA was extracted and analysed, using polymerase chain reaction, for expression of different cytokines potentially involved in the regulation of graft rejection [interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumour necrosis factor-alpha, interferon-gamma and transforming growth factor-beta]. In addition, using limiting dilution analysis, we investigated the frequency of allo-specific and third-party reactive cells producing IL-2 and IL-4 in vitro in different tissues of grafted mice following these treatments. The mAb treatment protocol which produced optimum increases in graft survival in naive versus immune mice was different, with anti-LFA-1:ICAM-1 superior for naive mice compared with anti-VLA-4:VCAM-1, and vice versa for immune animals. However, in each case, increased survival was associated with increases local to the graft in the frequency of occurrence of antigen-specific type-2 cytokine-producing cells.     

Induction of human airway smooth muscle apoptosis by neutrophils and neutrophil elastase

Neutrophils are an important component of airway inflammation and may interact with human airway smooth muscle cells (HASMC). We investigated the effect of neutrophils and of neutrophil-derived proteases on HASMC survival. When co-incubated with neutrophils (0.1-1 x 10(6) cells/ml), attachment of human ASMC was reduced to 12.3 +/- 4.3% compared with untreated controls after 72 h. HASMC showed nuclear condensation and fragmentation (41.6 +/- 8.1% compared with baseline of 3.1 +/- 0.4%), and the biochemical markers of apoptosis, annexin V binding (9.7 +/- 0.7%; baseline 1.1 +/- 0.3%) and cleaved caspase-3 expression, were observed. The proteolytic activity released by neutrophils was essential for the proapoptotic effect because inhibition of elastase activity by alpha(1)-antitrypsin and MeOSuc-Ala-Ala-Pro-Ala-CMK (MSACK) reduced HASMC apoptosis. Human neutrophil elastase (0.1-3 microg/ml) induced apoptosis of HASMC, as well as other neutrophil serine proteases, cathepsin G, and proteinase 3. Fibronectin degradation products were present in HASMC supernatants exposed to neutrophil-conditioned media and to neutrophil elastase. The local release of proteases from neutrophils present in airway smooth muscle cells may lead to HASMC apoptosis as a result of matrix degradation and loss of cell attachment. This may limit pathologic changes such as ASMC hyperplasia and extracellular matrix deposition seen in airway remodeling.     

Triple synchronous neoplasms in one kidney: report of a case and review of the literature

We report the case of a patient with three synchronous but histologically different primary renal tumors that were all in the same kidney. Two tumors were different subtypes of renal cell carcinoma (RCC), and the third was a variant form of angiomyolipoma. The patient was a 62-year-old man who was receiving antihypertensive drugs and came to our hospital for a regular check-up. Ultrasonography performed during the visit revealed a left renal mass, but the patient had no related symptoms. Subsequent computed tomography revealed two round, high-density masses, one in the mid-portion and the other in the lower pole of the left kidney, and multiple cysts in the right kidney and the liver. The mass in the mid-portion measured 3.3 x 3.0 x 2.8 cm, and the mass in the lower pole measured 1.7 x 1.1 x 0.9 cm. A left radical nephrectomy was performed. On gross examination, an additional ovoid nodule (0.6 cm in the greatest dimension) was found in the lower pole. Microscopically, the largest tumor consisted of a broad alveolar arrangement of large round cells with abundant eosinophilic or clear cytoplasm, distinct cell borders, and perinuclear halos, features consistent with chromophobe RCC. The smallest tumor was a conventional (clear-cell) RCC. The third tumor was composed solely of atypical epithelioid cells with prominent nucleoli and yellowish-brown to black pigments. The tumor cells were positive for melanin (Fontana-Masson stain), the melanoma marker HMB45, vimentin, smooth-muscle actin, and the macrophage marker CD68 and were negative for cytokeratin. This tumor was considered a pigmented epithelioid type of angiomyolipoma. The histologic, histochemical, and immunohistochemical features in this case confirmed the presence of three synchronous primary tumors, a chromophobe and a clear-cell type RCC and a pigmented epithelioid angiomyolipoma, all of which were in the same kidney. This case is the first of its type reported in the literature.     

Inhibition of inducible nitric oxide synthase expression by interleukin-4 and interleukin-13 in human lung epithelial cells.

Oral feeding of proteins causes peripheral T-cell tolerance, as revealed by reduced delayed-type hypersensitivity (DTH) reactivity after immunization. This type of tolerance can be due both to passive T-cell anergy and active immunosuppression. Using ovalbumin-fed mice we studied whether putatively immunostimulatory cytokines could break this state of mucosal tolerance. Cytokines were administered locally at the site of attempted sensitization. It was found that neither interleukin-2 (IL-2), interferon-gamma (IFN-gamma) nor granulocyte-macrophage colony-stimulating factor (GM-CSF) could restore the response to immunization. In contrast, local administration of IL-12 at the site of attempted immunization resulted in full recovery of DTH reactivity. The dichotomy between the two Th1 stimulatory cytokines IFN-gamma and IL-12 was also reflected by different effects on ovalbumin-specific antibody isotypes. Although both IFN-gamma and IL-12 downregulated serum IgG1-levels in tolerant mice, suggesting decreased ovalbumin-specific Th2 function, only local administration of IL-12 led to increased serum IgG2a levels. These results support the view that potentiation of Th1 effector function is critical for reversal of mucosal tolerance.     

The effect of beta adrenergic stimulation on QT and QTc interval in syncope children with or without coexisting ventricular arrhythmias

We investigated the effect of beta-adrenergic stimulation on the heart rate and QT interval in syncope children with or without coexisting ventricular arrhythmias (VA). Of the 24 children who presented with syncope or presyncope and showed negative tilt test, 13 were classified into a group with VA and the remaining 11 without VA. The provocative test was performed in bolus infusion and continuous infusion. RR, QT, and QTc intervals on routine 12-lead surface electrocardiogram were obtained during each stage of isoproterenol infusion. In all cases, malignant ventricular arrhythmia and syncope were not induced by isoproterenol provocative test. RR and QT intervals were shortened and QTc intervals were prolonged as the isoproterenol dose was increased in both groups and methods. The QTc interval reached its peak level after the bolus injection of 1.0 microgram and during the continuous infusion of 0.03 microgram/kg/min. The two groups showed no significant difference in the QTc interval change according to the infusion methods. This study indicates that changes in the heart rate and QT interval by beta-adrenergic stimulation were not different according to the coexisting ventricular arrhythmias in syncope children with negative head-up tilt test.     

Development of counterpulsation algorithm for a moving-actuator type pulsatile LVAD

A pulsatile left ventricular assist device (LVAD) was used to support the aortic blood pumping function of an injured left ventricle, and as a result helped its recovery. It is important to observe a left ventricle's pumping status and to adjust the operating status of a LVAD to reduce the left ventricle's pumping load and thus to enhance its recovery. To observe the left ventricle's pumping status, an electrocardiogram (ECG) signal is generally used because it is a result of the natural heart's blood pumping function. In this paper, we describe the development of an ECG based counterpulsation control algorithm that prevents simultaneous aortic blood co-pumping by a left ventricle and a moving-actuator type pulsatile LVAD and as a result, reduces the natural heart's pumping load. In addition, to verify the algorithm's applicability for LVAD control we designed three ECG based automatic pump control algorithms that use a developed counterpulsation control algorithm. These algorithms control the operating status of a LVAD automatically and, at the same time, maintain a counterpulsing status. The results of in vitro experiments show that the counterpulsing effect between a left ventricle and a LVAD was successfully produced and that the newly designed automatic pump control algorithms met their own control purposes with a counterpulsing effect.     

Randomized comparison of ovulation induction with and without intrauterine insemination in the treatment of unexplained infertility

The aim of this prospective randomized controlled study wasto determine the possible role of ovulation induction with intrauterineinsemination (IUI) in the treatment of unexplained infertility.A total of 100 patients were randomized to receive ovulationinduction with or without IUI. All patients were treated withlong-course gonadotrophinreleasing hormone analogue (GnRHa),starting in the luteal phase, and exogenous follicle stimulatinghormone (FSH) to induce follicular growth. Ovulation was inducedusing human chorionic gonadotrophin and timed intercourse (TI)was advised 24–48 h later or IUI was effected 36—48h later. Both the cycle fecundities (21.8 and 8.5%) and thecumulative ongoing pregnancy rates after three cycles (42 and20%) were significantly higher (P < 0.03) in the IUI groupthan in the TI group respectively. This is a clear indicationthat ovulation induction with IUI is an effective treatmentmethod for unexplained infertility, but ovulation inductionwith TI has a negligible impact in this large group of patients.