Age-dependent changes in Na current magnitude and TTX-sensitivity in the canine sinoatrial node

In rabbit, sodium current (I_Na) contributes to newborn sinoatrial node (SAN) automaticity but is absent in adult SAN, where heart rate is slower. In contrast, heart rate is high and I_Na is functional in adult mouse SAN. Given the slower heart rates of large mammals, we asked if I_Na is functionally active in SAN of newborn or adult canine heart. SAN cells were isolated from newborn (6-10 days), young (40-43 days) and adult mongrels. I_Na was observed in > 80% of cells from each age. However, current density was markedly greater in newborn, decreasing with age. At all ages, I_Na was sensitive to nanomolar tetrodotoxin (TTX); 100 nmol/L inhibited I_Na by 46.7%, 59.9% and 90.7% in newborn, young and adult cells, respectively. While high TTX sensitivity suggested the presence of non-cardiac isoforms, steady-state inactivation was relatively negative (midpoints − 89.7 ± 0.7 mV, − 95.1 ± 1.2 mV and − 93.4 ± 1.9 mV from newborn to adult). Consequently, I_Na should be unavailable at physiological potentials under normal conditions, and 100 nmol/L TTX did not change cycle length or action potential parameters of spontaneous adult SAN cells. However, computer modeling predicts the large newborn I_Na protects against excess rate slowing from strong vagal stimulation. The results show that canine SAN cells have TTX-sensitive I_Na which decreases with post-natal age. The current does not contribute to normal automaticity in isolated adult cells but can be recruited to sustain excitability if nodal cells are hyperpolarized. This is particularly relevant in newborn, where I_Na is large and parasympathetic/sympathetic balance favors vagal tone.     

The microbiological quality of air improves when using air conditioning systems in cars

Background  

Because of better comfort, air conditioning systems are a common feature in automobiles these days. However, its impact on the number of particles and microorganisms inside the vehicle - and by this its impact on the risk of an allergic reaction - is yet unknown.     

Combined vascular endothelial growth factor receptor/epidermal growth factor receptor blockade with chemotherapy for treatment of local, uterine, and metastatic soft tissue sarcoma

PURPOSE: Soft tissue sarcoma (STS) is a rare heterogeneous malignancy. Overall survival has been stagnant for decades, primarily because systemic therapies are ineffective versus metastases, the leading cause of STS lethality. Consequently, we examined whether tyrosine kinase receptors active in STS growth signaling might be blockable and whether multireceptor blockade might synergize with low-dose STS chemotherapy by therapeutically affecting STS cells and their associated microenvironment. EXPERIMENTAL DESIGN: Vandetanib (AstraZenca), a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, was evaluated alone and with chemotherapy in vitro and in vivo in three human STS nude mouse xenograft models of different STS locations (muscle, uterus, lung), stages (primary, metastatic), and subtypes (leiomyosarcoma, fibrosarcoma, uterine sarcoma: luciferase-expressing MES-SA human uterine sarcoma cells surgically implanted into uterine muscularis with bioluminescence tumor growth assessment; developed by us). RESULTS: In vitro, human STS cells were sensitive to vandetanib. Vandetanib alone and with chemotherapy statistically significantly inhibited leiomyosarcoma local growth and fibrosarcoma lung metastasis. Direct injection of MES-SA into nude mice uterine muscularis resulted in high tumor take (88%), whereas s.c. injection resulted in no growth, suggesting microenvironmental tumor growth modulation. Vandetanib alone and with chemotherapy statistically significantly inhibited uterine sarcoma growth. In all models, vandetanib induced increased apoptosis, decreased tumor cell proliferation, and decreased angiogenesis. CONCLUSIONS: Vandetanib has antitumor effects against human STS subtypes in vitro and in vivo, where it also affects the tumor-associated microenvironment. Given the urgent need for better systemic approaches to STS, clinical trials evaluating vandetanib, perhaps with low-dose chemotherapy, seem warranted.     

Integrins as Antimetastatic Targets of RGD-Independent Snake Venom Components in Liver Metastasis

Metastasis comprises several subsequent steps including local invasion and intravasation at the primary site, then their adhesion/arrest within the vessels of host organs followed by their extravasation and infiltration into the target organ stroma. In contrast to previous studies which have used aspartate-glycine-arginine (RGD) peptides and antibodies against integrins, we used rare collagen- and laminin-antagonizing integrin inhibitors from snake venoms to analyze the colonization of the liver by tumor cells both by intravital microscopy and in vitro. Adhesion of liver-targeting tumor cells to the sinusoid wall components, laminin-1 and fibronectin, is essential for liver metastasis. This step is inhibited by lebein-1, but not by lebein-2 or rhodocetin. Both lebeins from the Vipera lebetina venom block integrin interactions with laminins in an RGD-independent manner. Rhodocetin is an antagonist of α₂β₁ integrin, a collagen receptor on many tumor cells. Subsequent to tumor cell arrest, extravasation into the liver stroma and micrometastasis are efficiently delayed by rhodocetin. This underlines the importance of α₂β₁ integrin interaction with the reticular collagen I-rich fibers in liver stroma. Antagonists of laminin- and collagen-binding integrins could be valuable tools to individually block the direct interactions of tumor cells with distinct matrix components of the Disse space, thereby reducing liver metastasis.     

Nipple discharge without palpable tumor. Apropos of 46 cases

The authors report 46 cases of nipple discharge without any palpable lesion. The diagnostic is made, most of the time, by 3-views bilateral mammograms. The place of other examinations (ultrasonography, galactography) is reported. The cytology of the discharge, as well as its macroscopic appearance (bloody, serous or greenish), determine the surgical indications. Quadrantectomy centered around the discharging duct, is the procedure of choice in this disease, at the interface between diagnostic and treatment, in fact, if benign tumors (papillomas) or non tumoral diseases (fibrocystic mastopathy and duct ectasia) predominate, invasive or in-situ malignant lesions represent 13 p. cent of these 46 discharges, justifying the significance of this clinical sign.     

Study of the conduction system in a population of patients with sudden infant death syndrome

Summary The conduction system of 23 infant hearts, 15 of sudden infant death syndrome (SIDS) and eight of those dying from known cause, was serially sectioned. A left-sided His bundle was found more commonly in (SIDS) (eight of 15) than in the controls (two of eight). Taking into account a previous study in which a left-sided His bundle was found in only four of 32 hearts from all age groups, this is statistically significant and may be a factor promoting SIDS.This research was aided by grant HL-30558-02 from the National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.     

Trends in Belgian premature avoidable deaths over a 20 year period

STUDY OBJECTIVES: To analyse over a 20 year period the level and trends in the "EC avoidable death indicators". DESIGN: The Years of Potential Life Lost (YPLL) method applied to curative and preventive avoidable mortality indicators in Belgium for four successive five year periods, countrywide as well as by district, separately for women and men. Ratios of YPLL rates (age standardised) describe changes between 1974-78 and 1990-94. SETTING: Belgium for the periods 1974-78, 1980-84, 1985-89, 1990-94. PARTICIPANTS: All avoidable death cases aged 1-64. MAIN RESULTS: Ratio of YPLL rates indicated a more favourable development between 1974-78 and 1990-94 in the EC avoidable indicators than in all causes premature mortality. The EC avoidable mortality indicators have been assigned to two categories, curative indicators and preventive indicators. The best ratio of YPLL rates was found in curative indicators for men but the largest gains in YPLL rates over the periods come from the "preventive indicators" in men. For women, malignant neoplasm of the breast rose to the first ranked in 1985-1989 and 1990-1994, where it contributed to more years of YPLL loss than motor vehicle accidents, and malignant neoplasm of the trachea, bronchus and lung had risen to the fifth ranked since 1985-89. The order of the top causes for men did not change between 1974 and 1994, except for cirrhosis of liver, which rose from the fifth to the fourth rank. In the particular case of one "preventive indicator", malignant neoplasm of the trachea, bronchus and lung, the regional analysis of time trend between 1974-78 and 1990-94 showed more districts with a favourable development for both men and women in the Flemish region than in Wallonia. CONCLUSION: The YPLL method combined with the avoidable mortality indicators enabled us to compare the changes of curative and preventive EC avoidable indicators between 1974-78 and 1990-94. In the case of malignant neoplasm of the trachea, bronchus and lung, which is of major concern to the health promotion policies, changes over the periods have widened a "north/south" health contrast.     

Direct entry of the right superior vena cava into the left atrium with aneurysmal dilatation and stenosis at its entry into the right atrium with stenosis of the pulmonary veins: A rare case

Summary This is the first autopsied case reported in the English language literature wherein the right superior vena cava entered both atria with obstruction of the entry into the right atrium, aneurysmal dilatation of the proximal part of the superior vena cava, and entry of the stenosed right upper pulmonary vein into the aneurysmal sac. The aneurysmally dilated right superior vena cava communicated directly with the left atrium. In addition, the remainder of the pulmonary veins, all of which were markedly stenosed, entered the left atrium. The embryogenesis of this unique malformation is briefly discussed. Aided by grant HL 30558-01 from the National Heart, Lung and Blood Institute of the National Institutes of Health, Bethesda, Maryland.     

Schwannoma of a seminal vesicle

We present the first reported case of a schwannoma of the seminal vesicle that occurred in a 48-year-old man who presented with right lower quadrant abdominal pain. Computed tomography scan and magnetic resonance imaging revealed a mass in the patient's right seminal vesicle. The patient was also found to have a rising prostate-specific antigen level and underwent a transrectal ultrasound-guided biopsy of the prostate and seminal vesicles, which revealed prostate cancer and schwannoma of the seminal vesicle, respectively. Radical prostatectomy with en bloc removal of the seminal vesicle mass was performed and the patient has been free of disease 24 months postoperatively.     

The effect of contrast and luminance on mfERG responses in a monkey model of glaucoma

PURPOSE: To evaluate the effect of contrast and luminance attenuation on the multifocal electroretinogram (mfERG) responses of normal and glaucomatous eyes of cynomolgus monkeys. METHODS: Nine adult male cynomolgus monkeys with unilateral experimentally induced glaucoma were used. Hypertension-induced damage was confirmed by tomography of the optic disc. mfERGs were recorded with five different stimulus contrasts and/or luminance settings. The first-order and the first slice of second-order responses were analyzed. RESULTS: Waveforms of normal and glaucomatous eyes differed in shape and amplitude. Second-order responses contributed to first-order responses of the signals in the normal eyes, but made a negligible contribution to the signals in the glaucomatous eyes. Contrast and luminance attenuation affected both first- and second-order responses. The differences between signals in normal and glaucomatous eyes were sufficiently large for an unsupervised clustering algorithm to achieve accurate segregation. CONCLUSIONS: The observations in this study indicate that outer and inner retinal generators participate in first-order mfERG responses and that both inner and outer retinal contributors respond to contrast and luminance changes in stimulus. The hypertension-induced changes in the mfERG furthermore suggest damage to both inner and outer retina.