Pertussis: should we vaccinate post transplant?
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Adult↗
Biomedical subjects
F J Clark
Publications and source records attributed to F J Clark.
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.
Adult↗
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.
Disease-Free Survival↗
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.
AIDS-Related Opportunistic Infections↗
High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H.
T-cell prolymphocytic leukemia (T-PLL) is a chemotherapy-resistant malignancy with a median survival of 7.5 months. Preliminary results indicated a high remission induction rate with the human CD52 antibody, CAMPATH-1H. This study reports results in 39 patients with T-PLL treated with CAMPATH-1H between March 1993 and May 2000. All but 2 patients had received prior therapy with a variety of agents, including 30 with pentostatin; none achieved complete remission (CR). CAMPATH-1H (30 mg) was administered intravenously 3 times weekly until maximal response. The overall response rate was 76% with 60% CR and 16% partial remission (PR). These responses were durable with a median disease-free interval of 7 months (range, 4-45 months). Survival was significantly prolonged in patients achieving CR compared to PR or no response (NR), including one patient who survived 54 months. Nine patients remain alive up to 29 months after completing therapy. Seven patients received high-dose therapy with autologous stem cell support, 3 of whom remain alive in CR 5, 7, and 15 months after autograft. Stem cell harvests in these patients were uncontaminated with T-PLL cells as demonstrated by dual-color flow cytometry and polymerase chain reaction. Four patients had allogeneic stem cell transplants, 3 from siblings and 1 from a matched unrelated donor. Two had nonmyeloablative conditioning. Three are alive in CR up to 24 months after allograft. The conclusion is that CAMPATH-1H is an effective therapy in T-PLL, producing remissions in more than two thirds of patients. The use of stem cell transplantation to consolidate responses merits further study.
Adult↗
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.
Biomechanical Phenomena↗
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.
Humans↗
A metric for assessing acuity in positioning joints and limbs.
In this paper, we present a method for assessing the exactness of sensing and setting the positions of joints and limbs, using a measure we call target resolution. Target resolution, derived from information theory but ultimately based on variance, estimates the fewest number of discrete, equally spaced targets required within a range to provide the maximum possible information transfer from any target set. We argue that target resolution provides better insight into the exactness of position sense than does the usual measure of accuracy based on mean or constant error. Studies have shown that measures of mean error in setting or indicating positions of joints or limbs exhibit lability; they drift and show considerable sensitivity to factors such as previous positions of the limb and learning. We derive the equation for calculating target resolution and give example resolutions for several joints we have tested. Target resolution often gives a quite different impression of proprioceptive exactness than do measures of accuracy based on mean error.
Extremities↗
Treatment of proximal aortic hypertension after thoracic aortic cross-clamping in dogs. Phlebotomy versus sodium nitroprusside/isoflurane.
Thoracic aortic cross-clamping causes proximal aortic hypertension. Theoretically, the method used to treat hypertension can influence spinal cord perfusion pressure and neurologic outcome. Phlebotomy was compared to sodium nitroprusside/isoflurane in terms of ability to treat increased proximal mean aortic pressure (MAPp) after thoracic aortic cross-clamping in dogs. Dogs were assigned randomly to one of three groups depending on the method used to treat hypertension after cross clamping: 1) phlebotomy (n = 10); 2) sodium nitroprusside/isoflurane (n = 11); and 3) control (no treatment) (n = 8). In each dog, anesthesia was maintained with isoflurane in oxygen, 1.4% end-tidal. The thoracic aorta was occluded 2.5 cm distal to the left subclavian artery for 50 min and then was released. Hemodynamics, cerebrospinal fluid pressure (CSFP), and regional blood flows by the radioactive microsphere technique, were measured at 1) baseline; 2) 2 min after aortic cross-clamping; 3) after treatment of proximal aortic hypertension; 4) 5 min after aortic unclamping; and 5) 30 min after resuscitation. At 24 h, a neurologic assessment was performed. Thoracic aortic cross-clamping increased MAPp, decreased distal MAP (MAPd), and reduced lumbar spinal cord perfusion pressure (SCPPl), [SCPPl = MAPd - CSFP], in all three groups. Control of increased MAPp necessitated removal of 36 +/- 9 ml/kg of blood in the phlebotomy group. In the sodium nitroprusside/isoflurane group, sodium nitroprusside (16 micrograms.kg-1.min-1) was infused and end-tidal isoflurane concentration increased to 2.5 +/- 0.7%, restoring MAPp to baseline level.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Horner's syndrome as a complication of pacemaker insertion.
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Blepharoptosis↗
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)
Adult↗
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.
Ankle Joint↗
Teaching of physiology in American medical schools.
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Curriculum↗
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.
Adult↗
Role of intramuscular receptors in the awareness of limb position.
We studied proprioception with the ankle joint and the metacarpophalangeal (MCP) joint of the index finger of humans by use of a method that could distinguish a position sense from a movement sense. The test measured how subjects' ability to detect a fixed displacement of a joint varied with the rate of joint rotation. A position sense should not depend on the speed of joint placement; therefore slow rates of movement should not degrade subjects' ability to sense joint displacements. However, in the absence of a position sense, subjects would presumably rely on movement signals that do depend on the rate of rotation, and their ability to detect displacements should decrease when rate decreases. Subjects could sense small displacements of the ankle (+/- 3.5 degrees) and the MCP joint (+/- 2.5 degrees lateral excursions) with no decrement in performance at speeds as low as 0.25 degrees/min for the ankle and 0.5 degrees/min for the MCP joint (the slowest tested thus far). The findings confirm the existence of a position sense with these joints. Block of the ulnar nerve at the wrist, which paralyzes the interosseous muscles that adduct and abduct the MCP joint but presumably leaves skin and joint mechanisms unaffected, substantially impaired subjects' ability to detect the lateral excursions at slow speeds. Performance fell sharply at speeds less than 128 degrees/min and leveled off at approximately 20% detections at speeds less than 4 degrees/min. Increasing displacement to +/- 7 degrees did not improve performance. Block of the common peroneal nerve at the knee, which paralyzes the ankle dorsiflexor muscles, substantially impaired subjects' ability to detect the +/- 3.5 degrees displacements at slow speeds when the foot was positioned to slacken the plantarflexion muscles (which were not affected by the block). Performance fell sharply at speeds less than 256 degrees/min and approached zero at speeds less than 16 degrees/min. However, positioning the foot to stretch the plantarflexor muscles restored subjects' performance to near normal. Local anesthetic injected into the MCP joint space produced no observable effect on the ability to detect either slow or fast excursions. The joint anesthesia went unnoticed by the subject. We conclude that independent and separable senses exist for limb position and limb movement and that normal position sense requires sensory inputs from the muscles.
Adult↗
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.
Adult↗
Signaling of kinesthetic information by peripheral sensory receptors.
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Animals↗
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.
Action Potentials↗