Structure, function and clinical relevance of the cardiac conduction system, including the atrioventricular ring and outflow tract tissues.

It is now over 100years since the discovery of the cardiac conduction system, consisting of three main parts, the sinus node, the atrioventricular node and the His-Purkinje system. The system is vital for the initiation and coordination of the heartbeat. Over the last decade, immense strides have been made in our understanding of the cardiac conduction system and these recent developments are reviewed here. It has been shown that the system has a unique embryological origin, distinct from that of the working myocardium, and is more extensive than originally thought with additional structures: atrioventricular rings, a third node (so called retroaortic node) and pulmonary and aortic sleeves. It has been shown that the expression of ion channels, intracellular Ca(2+)-handling proteins and gap junction channels in the system is specialised (different from that in the ordinary working myocardium), but appropriate to explain the functioning of the system, although there is continued debate concerning the ionic basis of pacemaking. We are beginning to understand the mechanisms (fibrosis and remodelling of ion channels and related proteins) responsible for dysfunction of the system (bradycardia, heart block and bundle branch block) associated with atrial fibrillation and heart failure and even athletic training. Equally, we are beginning to appreciate how naturally occurring mutations in ion channels cause congenital cardiac conduction system dysfunction. Finally, current therapies, the status of a new therapeutic strategy (use of a specific heart rate lowering drug) and a potential new therapeutic strategy (biopacemaking) are reviewed.

Brain metastasis and carcinomatous meningitis from vulvar squamous cell carcinoma: case report.

BACKGROUND: Brain metastasis and carcinomatous meningitis from gynecological tumors are an uncommon event, usually related to choriocarcinoma, ovarian and cervical cancer. CASE: A 74-year-old woman was diagnosed with locally advanced vulvar squamous carcinoma. Initial therapy consisted of multiagent chemotherapy and vulvar, pelvis and groin irradiation. The patient subsequently developed widely spread metastatic disease including brain and meningeal metastases. CONCLUSION: The rising incidence of central nervous system metastasis in the last two decades is probably associated with treatment-related improvement in life expectancy. To our knowledge, this is the first case reported of brain metastases and meningeal carcinomatosis associated with vulvar squamous cell carcinoma.

Computer-controlled mechanical simulation of the artificially ventilated human respiratory system.

A mechanical lung simulator can be used to simulate specific lung pathologies, to test lung-function equipment, and in instruction. A new approach to mechanical simulation of lung behavior is introduced that uses a computer-controlled active mechatronic system. The main advantage of this approach is that the static and dynamic properties of the simulator can easily be adjusted via the control software. A nonlinear single-compartment mathematical model of the artificially ventilated respiratory system has been derived and incorporated into the simulator control system. This model can capture both the static and dynamic compliance of the respiratory system as well as nonlinear flow-resistance properties. Parameters in this model can be estimated by using data from artificially ventilated patients. It is shown that the simulation model fits patient data well. This mathematical model of the respiratory system was then matched to a model of the available physical equipment (the simulator, actuators, and the interface electronics) in order to obtain the desired lung behavior. A significant time delay in the piston motion control loop has been identified, which can potentially cause oscillations or even instability for high compliance values. Therefore, a feedback controller based on the Smith-predictor scheme was developed to control the piston motion. The control system, implemented on a personal computer, also includes a user-friendly interface to allow easy parameter setting.

Aerosol therapy and the fighting toddler: is administration during sleep an alternative?

Insufficient cooperation during administration of aerosols by pressurized metered dose inhaler (pMDI)/spacers is a problem in nearly 50% of treated children younger than 2 years. For these children, administration during sleep might be more efficient. However, it is unknown how much aerosol reaches the lungs during sleep. The aim of this study was to determine in vitro the lung dose in young children from a pMDI/spacer during sleep and while being awake. Breathing patterns were recorded by a pneumotachograph in 18 children (age 11 +/- 5.1 months) during sleep and wakefulness. Next, breathing patterns were replayed by a computer-controlled breathing simulator to which an anatomically correct nose-throat model of a 9-month-old child was attached. One puff of budesonide (200 microg) was administered to the model via a metal spacer. Aerosol was trapped in a filter placed between model and breathing simulator. The amount of budesonide on the filter (5 lung dose) was analyzed by HPLC. For each of the 36 breathing patterns, lung dose was measured in triplicate. The sleep breathing patterns had significantly lower respiratory rate and peak inspiratory flows, and smaller variability in respiratory rate, tidal volume, and peak inspiratory flows. Lung dose (mean +/- SD) was 6.5 +/- 3.2 and 11.3 +/- 3.9 microg (p = 0.004) for the wake and sleep breathing pattern, respectively. This infant model-study shows that the lung dose of budesonide by pMDI/spacer is significantly higher during sleep compared to inhalation during wake breathing. Administration of aerosols during sleep might, therefore, be an efficient alternative for uncooperative toddlers.

Estimation of expiratory time constants via fuzzy clustering.

OBJECTIVE: In mechanically ventilated patients the expiratory time constant provides information about respiratory mechanics. In the present study a new method, fuzzy clustering, is proposed to determine expiratory time constants. Fuzzy clustering differs from other methods since it neither interferes with expiration nor presumes any functional relationship between the variables analysed. Furthermore, time constant behaviour during expiration can be assessed, instead of an average time constant. The time constants obtained with fuzzy clustering are compared to time constants conventionally calculated from the same expirations. METHODS: 20 mechanically ventilated patients, including 10 patients with COPD, were studied. The data of flow, volume and pressure were sampled. From these data, four local linear models were detected by fuzzy clustering. The time constants (tau) of the local linear models (clusters) were calculated by a least-squares technique. Time constant behaviour was analysed. Time constants obtained with fuzzy clustering were compared to time constants calculated from flow-volume curves using a conventional method. RESULTS: Fuzzy clustering revealed two patterns of expiratory time constant behaviour. In the patients with COPD an initial low time constant was found (mean tau1: 0.33 s, SD 0.21) followed by higher time constants; mean tau2: 2.00 s (SD 0.91s), mean tau3: 3.45 s (SD 1.44) and mean tau4: 5.47 s (SD 2.93). In the other patients only minor changes in time constants were found; mean tau1: 0.74 s (SD 0.30), mean tau2: 0.90 s (SD 0.23), mean tau3: 1.04 s (SD 0.42) and mean tau4: 1.74 s (SD 0.78). Both the pattern of expiratory time constants, as well as the time constants calculated from the separate clusters, were significantly different between the patients with and without COPD. Time constants obtained with fuzzy clustering for cluster 2, 3 and 4 correlated well with time constants obtained from the flow-volume curves. CONCLUSIONS: In mechanically ventilated patients, expiratory time constant behaviour can be accurately assessed by fuzzy clustering. A good correlation was found between time constants obtained with fuzzy clustering and time constants obtained by conventional analysis. On the basis of the time constants obtained with fuzzy clustering, a clear distinction was made between patients with and without

Sex differences in uric acid metabolism in adults: evidence for a lack of influence of estradiol-17 beta (E2) on the renal handling of urate.

The serum urate concentration of adult women, which is lower than in men of a similar age, is thought to be related to a higher renal clearance of urate in women, possibly due to their higher plasma estrogen levels. Intersexual differences in the renal handling of uric acid was assessed in 9 normal adult women and 9 normal age-matched men. Women showed a significantly lower serum urate concentration as compared to men (3.5 +/- 0.3 v 4.9 +/- 0.7 mg/dL, P less than 0.001), higher fractional excretion of urate (9.8 +/- 1.0 v 7.3 +/- 0.8%, P less than 0.001), and significantly lower tubular urate postsecretory reabsorption (67.2 +/- 1.6 v 76.6 +/- 1.4% of secreted urate, P less than 0.01). To test whether plasma E2 has a uricosuric effect we administered estradiol valerate and estradiol benzoate to either oophorectomized or adult women. Plasma E2 levels and urinary total estrogen excretion increased significantly in both groups but the treatment failed to significantly modify serum urate or the fractional excretion of uric acid. Furthermore, in 4 normal adult women, the tubular phases that modulate the renal excretion of urate were not significantly influenced by increased plasma E2 levels. We conclude that in comparison to men of a similar age, the lower tubular urate postsecretory reabsorption of adult women is in accordance with the intersexual differences in uric acid metabolism. Plasma E2 does not influence renal handling of uric acid or serum urate levels.

Complete proximal tubular acidosis (Type 2, RTA) in chronic active hepatitis.

Fifteen patients with chronic active hepatitis (CAH) were tested in order to ascertain the site of tubular dysfunction in renal tubular acidosis (RTA) associated with CAH. Renal plasma flow and GFR were reduced in the patients compared to controls (P < 0.005). Underbasal and acidification conditions, twelve patients showed normal acid-base balance and net acid excretion, while three patients had basal hyperchloremic metabolic acidosis while passing alkaline urine and showing bicarbonaturia. A sustained acidification test showed adequate urinary acidification in these three patients. Bicarbonate loading carried out in two of the three patients showed a proximal tubular acidifying defect (Type 2 RTA), Distal RTA (Type 1 RTA) complicating CAH is widely known, but these data suggest that CAH can also involve the proximal convoluted tubule in isolation.