Janez Rozman

Differences between bisoprolol and carvedilol in patients with chronic heart failure and chronic obstructive pulmonary disease: a randomized trial

BACKGROUND Chronic obstructive pulmonary disease (COPD) frequently coexists in patients with chronic heart failure (CHF) and is a key factor for beta blocker underprescription and underdosing. This study compared effects of bisoprolol and carvedilol in patients with both conditions. METHODS This was a randomized open-label study, of bisoprolol and carvedilol during initiation and uptitration to target or maximal tolerated dose. Pulmonary function testing, 12-lead electrocardiogram, and N-terminal pro brain natriuretic peptide were measured at baseline and follow-up. RESULTS We randomized 63 elderly patients (73 ± 9 years, 81% men, left ventricular ejection fraction 33 ± 7%) with mild to moderate CHF (54% New York Heart Assocation class II) and moderate to severe COPD (76% Global initiative for chronic Obstructive Lung Disease stage 2). Target dose was tolerated by 31 (49%) patients and 19 (30%) patients experienced adverse events during follow-up (19% bisoprolol, 42% carvedilol, p = 0.045). Study medication had to be withdrawn in 8 (13%) patients (bisoprolol: 2 due to hypotension, 1 due to bradycardia; carvedilol: 2 due to hypotension and 1 due to wheezing, dyspnoea, and oedema, respectively). Forced expiratory volume in 1(st) second significantly increased in bisoprolol (1561 ± 414 ml to 1698 ± 519 ml, p = 0.046) but not carvedilol (1704 ± 484 to 1734 ± 548, p = 0.44) group. Both agents reduced heart rate (bisoprolol: 75 ± 14 to 68 ± 10, p = 0.007; carvedilol 78 ± 14 to 72 ± 12, p = 0.016) and had no effect on N-terminal pro brain natriuretic peptide. CONCLUSIONS Beta blockers frequently caused adverse events, and thus 49% of patients could tolerate the target dose. Bisoprolol induced demonstrable improvement in pulmonary function and caused less adverse events.

Multielectrode spiral cuff for ordered and reversed activation of nerve fibres

In this paper we present the modelling, design, and experimental testing of a nerve cuff multielectrode system for selective activation of fibres in superficial peripheral nerve trunk regions which is capable of activating fibres in physiological order. The multielectrode system consists of 45 platinum electrodes embedded within a self-curling spiral silicone sheet organized in fifteen longitudinal groups consisting of three electrodes spaced equidistally around the circumference of the cuff. Electrodes in the centre band acted as stimulating cathodes while the two electrodes of the same group in the two outer bands were connected together and corresponded to the position of a particular cathode, serving as anodes to block the nascent action potentials by membrane hyperpolarization. The interpolar distance was 6 mm on both sides, resulting in a total cuff length of about 20 mm. The cuff was constructed with a diameter to fit the size of the dog sciatic nerve. Preliminary animal testing of the nerve cuff was performed on the sciatic nerve of a Bigley female dog. In the 45-electrode stimulation system, biphasic cathodic first pulses with quasitrapezoidal-shaped cathodic and square anodic parts were delivered through the particular group of tripolar electrodes to effect both selective stimulation of motor axons within the gastrocnemius muscle fascicle, and differential block by membrane hyperpolarization. The test was repeated using rectangular cathodic first biphasic current pulses delivered monopolarly on the central electrode of the same group while connected anodes were replaced by a common anode situated elsewhere in the surrounding tissue. In both experiments an isometric torque in the ankle joint elicited by the gastrocnemius muscle was measured and compared.(ABSTRACT TRUNCATED AT 250 WORDS)

Multielectrode spiral cuff for selective stimulation of nerve fibres

In this paper we present the modelling, design, and initial experimental testing of a nerve cuff multielectrode system for selective stimulation of fibres in superficial peripheral nerve trunk regions which is capable of making a selective activation of multiple muscles. The developed multielectrode nerve cuff consists of 14 platinum stimulating electrodes embedded within a self-curling sheet of biocompatible insulation, exhibiting a spiral transverse cross-section. The spiral shape of the system is such that the number of stimulating electrodes which can be utilized depends on the diameter of the stimulated nerve. Nerves with a greater diameter automatically make use of more electrodes than thin ones. The development was based on results obtained by a histological examination of the peripheral nerves which were planned to be stimulated, and on models of excitation of myelinated nerve fibres. The modelling objectives were to determine the electric field that would be generated within a nerve trunk by a specific electrode. Moreover, the extent of initial excitation of the nerve fibres within the superficial region of the dog sciatic nerve elicited by a certain discrete stimulating electrode was predicted. For this purpose a calculation of activating function for six positions where the nerve fibres were supposed to lie within the longitudinally dissected sciatic nerve was performed. In two acute experiments on the sciatic nerve of the dog the objective was to characterize the effectiveness of the multielectrode system in monopolar selective stimulation of the superficial regions, innervating the gastrocnemius and tibialis anterior muscle. A selectivity preliminary tested by measuring the myoelectric activity of the gastrocnemius and tibialis anterior muscle after 2 months showed good results in both animals.

Heart function influenced by selective mid-cervical left vagus nerve stimulation in a human case study

Heart function influenced by selective mid-cervical left vagus nerve stimulation in a human case study

Regeneration of the radial nerve in a dog influenced by electrical stimulation.

The effect of biphasic electric fields on nerve regeneration that follows injury to the left radial nerve of a dog was examined using electromyography (EMG). The left and right radial nerves were crushed with a serrated hemostat and the stimulating electrodes were positioned proximally and distally relative to the site of the injury. The left nerves received rectangular, biphasic current pulses (30µA, 0.5Hz) through the lesion for two months. The right radial nerves were treated as controls and regenerated without electrical stimulation. EMG activity was recorded intramuscularly from left and right musculus extensor digitorum (from Medical dictionary) communis (MEDC). Results obtained at the end of the two-month stimulation period showed a significant difference between the EMG activity of the stimulated and the unstimulated MEDC suggesting that the electrical treatment enhanced the nerve regeneration.

Tremor amplitude and tremor frequency variability in Parkinson’s disease is dependent on activity and synchronisation of central oscillators in basal ganglia

Rest tremor is one of the four main clinical features of Parkinsons disease (PD), besides rigidity, bradykinesia and postural instability. While rigidity, bradykinesia and postural instability can be explained with changes in neurotransmitter concentrations and neuronal activity in basal ganglia, the pathogenesis of parkinsonian tremor is not fully understood. According to the leading hypothesis tremor is generated by neurons or groups of neurons in the basal ganglia which act as central oscillators and generate repetitive impulses to the muscles of the body parts involved. The exact morphological substrate for central oscillators and the mechanisms leading to their activation are still an object of debate. Peripheral neural structures exert modulatory influence on tremor amplitude, but not on tremor frequency. We hypothesise that rest tremor in PD is the result of two mechanisms: increased activity and increased synchronisation of central oscillators. We tested our hypothesis by demonstrating that the reduction in rest tremor amplitude is accompanied by increased variability of tremor frequency. The reduction of tremor amplitude is attributed to decreased activity and poor synchronisation of central oscillators in basal ganglia; the increased variability of tremor frequency is attributed to poor synchronisation of the central oscillators. In addition, we demonstrated that the recurrence of clinically visible rest tremor is accompanied by a reduction in tremor frequency variability. This reduction is attributed to increased synchronisation of central oscillators in basal ganglia. We argue that both mechanisms, increased activity of central oscillators and increased synchronisation of central oscillators, are equally important and we predict that tremor becomes clinically evident only when both mechanisms are active at the same time. In circumstances when one of the mechanisms is suppressed tremor amplitude becomes markedly reduced. On the one hand, if the number of active central oscillators is very low, the muscle-stimulating impulses are too weak to cause clinically evident tremor. On the other hand, if central oscillator synchronisation is poor, the impulses originating from different central oscillators are not in phase and thus cancel out, again leading to reduced stimulation of muscles and reduced tremor amplitude. Our hypothesis is supported by our measurements on patients with PD and by experimental data cited in the literature. The proposed two mechanisms could have clinical implications. New medical treatments, which would specifically target only one of the proposed mechanisms (oscillator activity or synchronisation), could be effective in reducing tremor amplitude and thus supplement established antiparkinsonian treatments.

A new method for selective measurement of joint movement in hand tremor in Parkinson's disease patients

Parkinsons disease (PD) is a progressive degenerative disorder of the central nervous system with tremor being one of its four main clinical features. Currently used methods can directly evaluate tremor amplitude and frequency but not joint movement in the affected limb. Measurement of joint movement facilitates the location of muscle groups that participate in PD tremor and this is important for treatment with local botulinum toxin injections. We developed and tested a method that measured tremor amplitude and frequency in a specific joint of the hand in PD patients. The tremor analysis method was based on force transducers adapted to record rest tremor of the wrist and metacarpophalangeal joints in two degrees of freedom for each joint. Direct measurements of joint movement in the hand can evaluate tremor amplitude and frequency and also locate the muscle groups that are most active in tremor movement, thus enabling their local treatment.

Evaluation of the strength of elbow flexors in patients with neuromuscular diseases

In planning the optimum treatment for patients with neuromuscular diseases (NMD), it is essential to know as much as possible about their functional state. Assessment of the strength of certain muscles is the most direct measure of motor deficiency. In the development of normative data needed for patients with NMD, the use of torque measurements is required. Forty-nine patients (31 men and 18 women),f rom 18 to 54 years (mean age 33 +/- 8.9 years), were included in the study. Five groups of patients, each having one of five different NMDs, were formed. We tested unilaterally the biceps brachii muscle that normally generates the highest torque. For this purpose an eletronic brace enabling isometric measurements of torque during elbow flexion was designed. The patients produced three maximum voluntary elbow flexions that lasted about 3 s and separated by a pause of about 3 s. Force development was rapid with continuous build-up and isometric. About 15 s later the patients produced the last maximum voluntary elbow flexion, keeping it as stable aspossible for a period of 30 s. Patients with mitochondrial myopathy (MM), having the shortest mean half fatigue time (4.3 s), elicited the highest mean torque in both short maximum voluntary elbow flexions (1.34 Nm) as well as in the 30 s-long maximum voluntary elbow flexions. In contrast, patients with facioscapulohumeral muscular dystrophy (MD-FSH), having the longest mean half-fatigue time (15.4 s), elicited the lowest mean torque in both the short maximum voluntary (0.29 Nm) as well as in 30 s-long maximum voluntary elbow flexions. Patients with Becker muscular dystrophy (MD-B), having a mean half-fatigue time (11.1 s) slightly shorter than the patients with MD-FSH, elicited a higher mean torque in both the short (0.82 Nm) and the 30 s-long elbow flexions. Finally, patients with limb-girdle muscular dystrophy (MD-RM) and spinal muscular atrophy type 3 (SMA3), having a similar mean half-fatigue time (6.9 s for patients with MD-RM and 7.4 s for patients with SMA3), also elicited similar torque in both short (0.45 Nm for patients with MD-RM and 0.65 Nm for patient with SMA3) and 30 s-long elbow flexions. The results of the study show that the methodology developed to quantitative measure the torque of elbow flexions in patients with NMD enables the characteristics and natural course of NMD to be more objectively documented. Accordingly, the optimum treatmentforpatients with NMD could be restored.In planning the optimum treatment for patients with neuromuscular diseases (NMD), it is essential to know as much as possible about their functional state. Assessment of the strength of certain muscles is the most direct measure of motor deficiency. In the development of normative data needed for patients with NMD, the use of torque measurements is required. Forty-nine patients (31 men and 18 women), from 18 to 54 years (mean age 33 - 8.9 years), were included in the study. Five groups of patients, each having one of five different NMDs, were formed. We tested unilaterally the biceps brachii muscle that normally generates the highest torque. For this purpose an electronic brace enabling isometric measurements of torque during elbow flexion was designed. The patients produced three maximum voluntary elbow flexions that lasted about 3 s and separated by a pause of about 3 s. Force development was rapid with continuous build-up and isometric. About 15 s later the patients produced the last maximum voluntary elbow flexion, keeping it as stable as possible for a period of 30 s. Patients with mitochondrial myopathy (MM), having the shortest mean halffatigue time (4.3 s), elicited the highest mean torque in both short maximum voluntary elbow flexions (1.34 Nm) as well as in the 30 s-long maximum voluntary elbow flexions. In contrast, patients with facioscapulohumeral muscular dystrophy (MD-FSH), having the longest mean half-fatigue time (15.4 s), elicited the lowest mean torque in both the short maximum voluntary (0.29 Nm) as well as in 30 s-long maximum voluntary elbow flexions. Patients with Becker muscular dystrophy (MD-B), having a mean half-fatigue time (11.1 s) slightly shorter than the patients with MD-FSH, elicited a higher mean torque in both the short (0.82 Nm) and the 30 s-long elbow flexions. Finally, patients with limb-girdle muscular dystrophy (MD-RM) and spinal muscular atrophy type 3 (SMA3), having a similar mean half-fatigue time (6.9 s for patients with MD-RM and 7.4 s for patients with SMA3), also elicited similar torque in both short (0.45 Nm for patients with MD-RM and 0.65 Nm for patients with SMA3) and 30 s-long elbow flexions. The results of the study show that the methodology developed to quantitatively measure the torque of elbow flexions in patients with NMD enables the characteristics and natural course of NMD to be more objectively documented. Accordingly, the optimum treatment for patients with NMD could be restored.

Modulation of hormone secretion by functional electrical stimulation of the intact and incompletely dysfunctional dog pancreas

The purpose of the present study was to modulate the secretion of insulin and glucagon in Beagle dogs by stimulation of nerves innervating the intact and partly dysfunctional pancreas. Three 33-electrode spiral cuffs were implanted on the vagus, splanchnic and pancreatic nerves in each of two animals. Partial dysfunction of the pancreas was induced with alloxan. The nerves were stimulated using rectangular, charge-balanced, biphasic, and constant current pulses (200 micros, 1 mA, 20 Hz, with a 100-micros delay between biphasic phases). Blood samples from the femoral artery were drawn before the experiment, at the beginning of stimulation, after 5 min of stimulation, and 5 min after the end of stimulation. Radioimmunoassay data showed that in the intact pancreas stimulation of the vagal nerve increased insulin (+99.2 microU/ml) and glucagon (+18.7 pg/ml) secretion and decreased C-peptide secretion (-0.15 ng/ml). Splanchnic nerve stimulation increased insulin (+1.7 microU/ml), C-peptide (+0.01 ng/ml), and glucagon (+50 pg/ml) secretion, whereas pancreatic nerve stimulation did not cause a marked change in any of the three hormones. In the partly dysfunctional pancreas, vagus nerve stimulation increased insulin (+15.5 microU/ml), glucagon (+11 pg/ml), and C-peptide (+0.03 ng/ml) secretion. Splanchnic nerve stimulation reduced insulin secretion (-2.5 microU/ml) and increased glucagon (+58.7 pg/ml) and C-peptide (+0.39 ng/ml) secretion, and pancreatic nerve stimulation increased insulin (+0.2 microU/ml), glucagon (+5.2 pg/ml), and C-peptide (+0.08 ng/ml) secretion. It was concluded that vagal nerve stimulation can significantly increase insulin secretion for a prolonged period of time in intact and in partly dysfunctional pancreas.

Recording of ENGs from the nerves innervating the pancreas of a dog during the intravenous glucose tolerance test

Electroneurograms (ENGs) from the vagus nerve (VN), the splanchnic nerve (SN) and the pancreatic nerve (PN) innervating the pancreas of a dog, were recorded with chronically implanted 33-electrode spiral cuffs (cuff) before and after the pancreas were stimulated with intravenously (i.v.) administered glucose. In the cuffs platinum electrodes were arranged in three parallel spiral groups containing 11 electrodes on the inner surface. The cuffs had an inner diameter of 2 mm and a length of 18 mm. In a two-year study, the cuffs were implanted into two Beagle dogs and were also used for pancreatic stimulation, although this is not described in this paper. In the VN, the cuff was installed on the nerve at the neck, whilst in the SN, the cuff was installed on the nerve before the celiac ganglion, and in the PN, the cuff was installed on the nerve just before it enters the pancreas. Six months after implantation, when the model of interpretation of the results was developed, three recordings of ENG in each animal were conducted. The first one was conducted in the unstimulated pancreas while the second and the third were conducted 1 and 8 min after a known amount of glucose was i.v. administered. Since the results obtained in both animals were actually quite similar, we present the results obtained in one animal. To evaluate the changes in superficial activity of the nerves, elicited by the administration of glucose, the power spectra corresponding to ENGs, recorded from the nerves before and after the administration of glucose, were integrated within the band of frequencies ranging from 1 to 5 kHz. Accordingly, the magnitude of the integrated power spectrum (MIPS), corresponding to the ENG recorded from the SN before administration of glucose, was 2.863 au. One minute after glucose was administered the value fell to 2.795 au while 8 min after the administration the value returned to 2.8 au. The MIPS corresponding to the ENG recorded from the PN before the administration of glucose was 3.236 au. One minute after the administration the value fell to 2.901 au while 8 min after the administration the value rose to 3.009 au. The MIPS, corresponding to the ENG recorded from the VN before the administration of glucose, was 3.656 au. One minute after the administration the value fell to 3.565 au. Eight minutes after the administration the value rose to 3.689 au. The results show that 1 min after glucose was administered superficial activity in all three nerves was reduced while 8 min after administration the activity in the nerves returned to the same level of activity before the glucose was administered. This information could be effectively used in a further study of pancreatic innervation and its function. Moreover, the results suggest that cuffs could also be useful in recording the ENGs from other nerves of the autonomic nervous system that innervate various glands and internal organs.