Recovery of renal function after autologous stem cell transplantation in myeloma patients with end-stage renal failure.

The disease-free survival of patients with myeloma and severe renal failure after high-dose melphalan and autologous stem cell rescue is similar to those with normal renal function at the time of the autograft. However, recovery of renal function after intensive treatment is uncommon and patients with end-stage renal failure continue to be dialysis-dependent. We report two patients with myeloma who required regular haemodialysis from diagnosis, but became dialysis-independent after a high-dose melphalan autograft. Thus, in some patients, renal function may be partially salvageable despite the requirement for dialysis at the time of autografting.

Massive hepatosplenomegaly caused by Penicillium marneffei associated with human immunodeficiency virus infection in a Thai patient.

A 29 year old Thai woman presented with non-specific features and examination revealed left upper zone consolidation and hepatosplenomegaly. The initial clinical differential diagnosis included tuberculosis and melioidosis. She died four days after admission, while still under investigation. Postmortem examination revealed antibodies to human immunodeficiency virus, disseminated Penicillium marneffei infection, and Salmonella enteritidis infection. Penicillium marneffei is a well described AIDS defining pathogen in South East Asia but is very rare in the UK. Appropriate antifungal treatment may be associated with a successful outcome. Increased awareness of this clinical association may enable correct diagnosis in affected patients from South East Asia presenting within the UK.

Systems for producing precise movements of a joint over a wide range of speeds and displacements for tests of a static-position sense.

This report describes 3 types of apparatus that were used to produce precise movements of a joint over a wide range of speeds and angles. The designs feature an ability for ultra slow rotation of the joint (fractions of a degree per min) with a minimum of extraneous cues. Two designs use servo-controlled DC motors configured as velocity servos and a third design uses a galvanometer motor configured as a position servo. Originally designed for use with humans in studies of proprioception with the ankle and two joints of the index finger (the metacarpophalangeal joint and proximal interphalangeal joint), the apparatuses should be useful in a variety of applications where precise control of velocity and position is needed.

The number of human peripheral blood CD4+ CD25high regulatory T cells increases with age.

Ageing is associated with evidence of immune deficiency and dysregulation. Key changes in the immune system with ageing include a progressive reduction in naive T cell output associated with thymic involution and peripheral expansion of oligoclonal memory T cells. These features are associated with evidence of impaired immune responsiveness both in vitro and in vivo, termed immune senescence. CD4+ CD25+ T cells have recently been recognized as mediators of peripheral immune regulation and play a role in the control of autoimmune and pathogen-specific immune responses. The significance of CD4+ CD25+ regulatory T cells in the context of immunosenescence is not known. We have investigated the number, phenotype and function of CD4+ CD25+ T cells in healthy volunteers over a wide age range. We demonstrate that the number of CD4+ CD25+ and CD4+ CD25high T cells in healthy volunteers increases with age. In both age groups CD4+ CD25+ T cells showed a phenotype consistent with that described for regulatory T cells. Further analysis of CD4+ CD25high T cells in young and elderly donors showed equivalent expression of intracellular CTLA-4 and surface expression of activation markers. In vitro, functional titration assays of CD4+ CD25high T cells demonstrated equivalent regulatory function in both young and elderly donors, with suppression of proliferation and cytokine production in response to polyclonal T cell stimulation. These observations demonstrate an increase in peripheral blood CD4+ CD25high regulatory T cells associated with ageing. The relevance of these expanded cells in relation to the immune senescence seen in the elderly as yet remains unclear.

Information signaled by sensory fibers in medial articular nerve.

Responses of 331 individual medial articular nerve fibers innervating the cat knee joint were tested to bending the joint over its entire range and to pressing on the tissues of the joint. The 331 fibers were classified into five groups on the basis of their discharge characteristics: slowly adapting (64), phasic (103), Pacinian corpuscle-like (12), weakly activated (39), and nonactivated (113). Five of the slowly adapting and all twelve of the Pacinian corpuscle-like receptors responded at intermediate joint angles. The remainder responded, if at all, only near the extremes of joint bending or twisting. Many of these same receptors could be activated by pressing about the knee. Sometimes gentle pressure on the focus sufficed to produce a vigorous discharge. The properties of these receptors are considered to be consistent with the hypothesis that articular mechanoreceptors do not signal joint angle but are involved in deep-pressure sensations.

Slowly adapting receptors in cat knee joint: can they signal joint angle?

Afferent activity in the lateral (LAN), medial (MAN), and posterior (PAN) articular nerves supplying the cat knee joint was studied at intermediate positions of the joint that included most of its working range. The discharge was analyzed only while the joint was stationary. The small LAN showed negligible tonic activity at intermediate angles (as determined by gross recording) and was not studied further.

On the regulation of depth and rate of breathing.

1. The relationships between the depth of a breath and the durations of the inspiratory and expiratory phases have been studied in cat and in man during rebreathing, and in cat using artificial inflations of different magnitudes and timings.2. In the cat, the apparent volume threshold for termination of inspiration (Hering-Breuer threshold) decreased with time from the onset of the inspiratory phase.3. Both in rebreathing experiments and with artificially imposed inflations in the cat, the inspiratory duration T(I) was dependent upon tidal volume V(T), and this dependence could be expressed by a hyperbolic relationship of the form (V(T)-V(0)) T(I) = C where V(0) and C are constants.4. The time course of this ;Hering-Breuer' threshold was dependent on intact vagus nerves. After vagotomy the inspiratory duration remained essentially constant with changes in tidal volume produced either by artificial inflation or by the increased respiratory drive due to accumulation of CO(2) during rebreathing.5. In man during rebreathing, the relation between volume and inspiratory duration typically showed two different characteristics. 1, at tidal volumes up to 1.5-2 times eupnoeic values, inspiratory duration did not change as tidal volume increased in response to increased P(CO2). This range of operation has been designated range 1. 2, as tidal volume increased above this range 1 a second range designated range 2 was observed where inspiratory duration was volume dependent in the same manner as in the cat.6. In cat under pentobarbitone anaesthesia, a range 1 operation was not seen except after vagotomy. However, under urethane anaesthesia a range 1 plus a range 2 operation could be seen.7. The differences between cat and man appeared to be largely quantitative rather than qualitative.8. In both cat and man, expiratory duration was dependent on inspiratory duration, usually with a linear relationship.9. The experimental results were assembled in the form of an inspiratory characteristic and a timing relationship that serve as a model of the respiratory mechanisms controlling the depth and rate of breathing. The model predicts that the depth and duration of a breath are related in a definite manner fixed by the system characteristics and that ventilation is adjusted by setting the appropriate operating point on these characteristics. The operating point is determined primarily by how quickly lung volume increases, i.e. the rate of increase of inspiratory motor activity.

Models of behaviors when detecting displacements of joints.

This report describes two models of human behavior when detecting displacements of joints that allow one to compare and integrate findings from different proprioception tests in a quantitative way. Results from various tests have led to different and often conflicting conclusions about proprioceptive behaviors and their underlying neural mechanisms. However, it has been impossible to compare data and conclusions in any meaningful way due to lack of a suitable analytical framework to accommodate important differences in procedures used in the various tests. These models can provide one such framework. The models, developed using data from proprioception tests reported in the literature, describe how the amplitude and velocity of joint excursions, and the subject bias expressed as false alarm rate, affect the detectability of displacements of joints. Two models were needed to represent observed behaviors: one based on velocity signals alone (the velocity model) and the other based on both velocity and positional signals (the displacement-velocity model). To simulate the detection-decision process subjects used to determine whether a joint was displaced, we adapted strategies from signal detection theory. The models characterized reported behaviors from disparate proprioception tests remarkably well, requiring only 3 degrees of freedom in the velocity case, and 4 in the displacement-velocity case.

Dorsal column projection of fibres from the cat knee joint.

1. Stimulation of the cervical dorsal columns excited an average of nine knee joint fibres in the cat posterior articular nerve, eleven fibres in the cat medial articular nerve and thirteen fibres in the monkey posterior articular nerve.2. Joint fibres projecting to cervical levels were shown to be rapidly adapting by recording with micro-electrodes from single fibres in intact cat posterior articular nerves. The numerous slowly adapting fibres could not be antidromically excited from the cervical dorsal columns.3. Several control experiments suggested that the antidromic stimulation method accurately defined the dorsal column projection of joint fibres.

Characteristics of knee joint receptors in the cat.

1. The conduction velocities of 278 posterior articular nerve fibres studied in dorsal root filaments ranged from 10 to 110 m/sec. The conduction velocities were distributed similarly to posterior articular nerve fibre diameters determined histologically.2. Two hundred and nine fibres were slowly adapting. Of these, 140 responded only at both marked flexion and marked extension, forty-seven responded only during flexion and twelve only during extension. Four slowly adapting fibres were activated specifically at intermediate joint positions. Outward twist of the tibia (abducting the foot) enhanced the discharge of most slowly adapting joint fibres.3. Two rapidly adapting receptor types were noted. Pacinian corpuscle-like receptors (fourteen fibres) responded transiently to joint movement in any direction regardless of initial position. Phasic joint receptors (thirty fibres) were rapidly adapting at most joint positions but could give a low rate sustained discharge when strongly stimulated.4. Six slowly adapting posterior articular nerve fibres responded to succinylcholine, suggesting that they originated from muscle spindles. Spindle-like receptors were usually tonically active at intermediate joint positions.5. Eleven slowly conducting myelinated fibres responded only to extreme joint movement, which was probably noxious.

The contribution of articular receptors to proprioception with the fingers in humans.

1. Whether joint receptors contribute demonstrably to proprioception has remained uncertain. Therefore, we tested whether an articular contribution to movement sense could be revealed if the total sensory input available to signal joint movement were reduced by eliminating movement signals from muscles. With a reduced sensory input, whatever contribution articular receptors made to proprioception ought to assume a greater-than-normal importance, and any effect of eliminating articular inputs should become more apparent. The distal interphalangeal joint of the middle finger was used, because the muscles could be decoupled from this joint by positioning the fingers to slacken the tendons. 2. To further enhance the possibility for observing an effect of eliminating articular contributions, we planned to test movement sense at positions of the joint in which the articular receptors would be most active. However, the response properties of receptors in primate finger joints were unknown, so we examined activity of receptors in finger joints of monkeys prior to testing humans. 3. Activity of receptors in interphalangeal joints of monkeys was measured over a wide range of positions before and during local anesthesia of the joint. Little response was seen over intermediate positions, but activity increased as the joint approached full flexion or full extension in much the same manner as responses previously observed with receptors in the knee, elbow, wrist, and hip joints. Local anesthetic injected into the joint space abolished the nerve activity. 4. Proprioception was tested in humans before and during local anesthesia of the joint using a movement-detection paradigm.(ABSTRACT TRUNCATED AT 250 WORDS)

Awareness of knee joint angle under static conditions.

The ability of subjects to match the angle of a passively positioned knee joint by active positioning of the opposite leg is nearly constant with time from 15s to 3 min. However, their ability to match this angle from memory is equally good. Thus, knowledge of joint angle after movement has ceased does not necessarily require ongoing input from tonic peripheral receptors.

Response of soleus Ia afferents to vibration in the presence of the tonic vibration reflex in the decerebrate cat.

1. Micro-electrode recordings were made from single Ia afferents in the intact nerve to the soleus muscle in the decerebrate cat while the muscle was developing a tonic vibration reflex. This was done in order to test how effectively the afferents were excited by the vibration, and to see if any insecurity in driving might be related to tremor.2. When the amplitude of vibration was 50 mum, and the tonic vibration reflex was reasonably well developed (> 1 N of active tension) all but one of forty-four Ia afferents were driven 1:1 by the vibration. Most were still driven by 30 mum vibration. The vibration, consisting of a train of discrete pulses at 150 Hz, was applied longitudinally in combination with a stretch of 1 mm to make the muscle taut.3. If the reflex was poorly developed (active tension < 1 N) the driving was on average less secure. However, fourteen of eighteen afferents then studied were still driven 1:1 by 50 mum vibration. The lower level of excitation by vibration was thought to be due to a deficiency of spontaneous fusimotor activity, because stroking the cat's tail or other similar gentle manipulation led each of the three misbehaving afferents so tested to be driven securely by 50 mum vibration; at the same time the reflex tension increased.4. Additional, indirect evidence favouring widespread security of Ia driving by 50 mum vibration in the presence of the reflex was obtained by modulating the amplitude of the 150 Hz vibration with a 7-10 Hz square wave and detecting any tension fluctuations at that frequency by spectral analysis. Small degrees of modulation (e.g. < 10%) produced little if any effect, although larger depths of modulation had a powerful action.5. When the amplitude of vibration was reduced to permit insecure driving but still to elicit a reflex response, the fluctuations in Ia firing pattern were unlike those previously seen in the de-efferented muscle. Spectral analysis showed that these firing fluctuations bore a general similarity to the tremor in the same preparation, but measurement of coherence demonstrated that the tremor and Ia firing were not well related. This was probably because individual Ia afferents were primarily influenced by local factors, and provides further evidence against the tremor of this preparation being attributable to the action of the stretch reflex.

Motor unit firing and its relation to tremor in the tonic vibration reflex of the decerebrate cat.

1. The discharge of single motor units has been recorded from the soleus muscle of the decerebrate cat during the tonic vibration reflex elicited isometrically, to further understanding of the tremor that is seen in the reflex contraction. The reflex was elicited by pulses of vibration of 50 micrometers amplitude at 150 Hz, and up to four units were studied concurrently. 2. Individual units fired rather regularly and at a low frequency (range 4-14 Hz). The rate of firing of any unit normally fell within the frequency band of the tremor recorded at the same time. On comparing different preparations a higher frequency of tremor was associated with a higher frequency of motor firing. 3. The responses of pairs of motor units recorded concurrently during repeated production of the reflex were compared by cross-correlation analysis; over 1000 spikes from each train were normally used for this. The major of the cross-correlograms were flat with no overt sign of any synchronization between the units other than that due to the vibration. 4. Clear indications of correlated motor unit firing could be produced deliberately by modulating the amplitude of vibration at a frequency comparable to that of the normal tremor and thereby introducing a rhythmic component into the tonic vibration reflex. 5. About 20% of the cross-correlograms obtained during normal tremor showed varying amounts of an irregular 'waviness' suggesting a possible correlation between the times of firing of a pair of units. But such waves never developed steadily throughout the period of analysis, in contrast to the comparable waves produced on modulating the vibration. Similar waves were seen on cross-correlating a motor unit with an electronic oscillator, confirming that their occurrence does not necessarily demonstrate the existence of active neural interactions. 6. It is concluded that there is no strong and widespread neural synchronizing mechanism active during the tonic vibration reflex, although the possibility of some weak neural interactions has not been excluded. The findings favour the idea that the tremor in this preparation is simply the inevitable result of motor units discharging asynchronously, but at closely similar subtetanic frequencies.

Proprioception with the proximal interphalangeal joint of the index finger. Evidence for a movement sense without a static-position sense.

Proprioceptive ability with the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints of the index finger in human subjects was examined using a method that could assess static-position sense independently of movement sense (Clark et al., 1985). The similarity in location and function of these joints would suggest similar proprioceptive mechanisms, but proprioceptive ability was found to be quite different for the two joints. The method of distinguishing a static-position sense from a movement sense was based on whether a subject's ability to detect a small change in joint position was impaired when the rate of rotation was progressively reduced. An awareness of static-position should not depend on the rate at which a joint is placed into position. However, if subjects use movement signals to detect changes in joint position, slowing the rate of displacement should reduce the intensity of these signals and make the displacements more difficult to detect. This method indicated a static-position sense with the MCP joint but only a movement sense with the PIP joint. It was confirmed that sensory input from regions of skin not stretched or deformed by rotation of the joint can influence proprioceptive sensibility with the fingers. Anaesthesia of the tip of the index finger or of the thumb blunted subject's perceptions of movement of the PIP joint of the index finger. However, anaesthesia of the PIP joint itself had no observable effect on the ability to sense movement of the joint.

Extrinsic muscles of the hand signal fingertip location more precisely than they signal the angles of individual finger joints.

Studies have demonstrated that muscle spindle organs provide the majority of the proprioceptive information available to the nervous system about limb position. Other studies suggest that a sense of position may be lacking in the fingers, as subjects were unaware of rather large excursions of finger joints if the excursions were made slowly enough. We sought to investigate the basis for this unexpected finding with a biomechanical model of the human long finger and the forearm muscles which actuate it, in order to study potential contributions of spindle organs in the extrinsic muscles of the hand to a sense of position of the finger. The model, based on cadaver data, allowed us to determine how precisely estimates of the lengths of the extrinsic finger muscles can be transformed into estimates of: (1) the flexion/extension angles of the individual finger joints, and (2) the location of the fingertip in the flexion/extension plane. We found that, for some finger positions, length information from all three extrinsic muscles was not sufficient to precisely estimate the flexion angles of all finger joints. Precision of joint angle estimates could be as poor as +/- 18% of joint range of motion. However, length information from just two of the extrinsic muscles taken together could always provide information sufficient to estimate the location of the fingertip relative to the metacarpophalangeal joint within a reasonably small tolerance (+/- one-half thickness of the fingertip). Furthermore, it was possible to make this estimate without determining any of the finger joint angles. These results suggest that spindles in the extrinsic muscles alone can signal fingertip location, even though they may not provide sufficient information to estimate the individual joint angles that set the position of the fingertip. Thus, an absence of position sense for individual joints (the sense many studies have tried to measure) may say little about a sense of location of the tip of the finger.

Microstimulation of single tactile afferents from the human hand. Sensory attributes related to unit type and properties of receptive fields.

Tungsten microelectrodes were inserted percutaneously into the median nerve of alert human subjects for recording and stimulation of single nerve fibres. Impulses from mechanoreceptive units in the glabrous skin of the hand were recorded and single afferents were characterized with respect to unit type (FA I, FA II, SA I, and SA II), as well as size and shape of receptive field, and force threshold. The electrode was then reconnected to an electrical stimulator and short pulse trains (0.25 to 0.5 s, 20 to 100 Hz) were delivered at successively increasing current intensity, while the subject was asked to report any sensation that he noticed in the hand. The first sensation was always that of a localized skin deformation within a small area, typically 2 to 3 mm in diameter, often coinciding with the receptive field of the recorded unit. Spatial matching was also found in many cases for the size, shape and orientation of the perceptive and receptive fields, strongly suggesting that the sensation was accounted for by the recorded unit that had been selectively activated by the current pulses. There were clear differences between group data associated with the four types of units with regard to the quality of the percepts. Vibratory sensation was reported with all FA II units and was common with FA I units, whereas a sustained indentation was often associated with SA I units. Indirect evidence suggested that activation of SA II units usually did not elicit a sensation. It was confirmed that a single impulse in a single FA I unit may elicit a sensory response in the attending subject, whereas a much larger input was required from SA I units, which are also less sensitive to mechanical stimuli. This was one of several findings supporting the impression that differential receptive properties, even within a group of afferents, were associated with different sensory responses. It was concluded that a train of impulses in a single tactile unit may produce within the brain of the subject a construct which specifies with great accuracy the skin area of the unit's terminals as well as a tactile subquality which is related to unit properties.