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Biomedical subjects

R A Lehman

Publications and source records attributed to R A Lehman.

At least 19 recordsLinked to original sources
PubMed2000

Segmental limb reconstruction after tumor resection.

Limb salvage of large segmental and osteoarticular defects after tumor resection has become the standard of care for most patients with musculoskeletal tumors because overall survival is the same when compared with that seen in amputation patients. This study examines limb salvage for the surgical management of large segmental defects in terms of local recurrence, complications, and functional outcome in both primary and metastatic lesions. We retrospectively identified 32 patients with benign or malignant tumors of bone who underwent resection and limb salvage reconstruction by means of a custom or modular metal implant between 1985 and 1995. The most common tumor sites were the proximal femur (41%), distal femur (37.5%), and proximal humerus (12.5%). Primary bone lesions accounted for 18 patients (56%); metastatic disease accounted for 14 patients (44%). Osteosarcoma (n = 11) and chondrosarcoma (n = 3) were the most frequent primary tumors. The overall limb salvage rate (91%) was high, yet complications (28%) were common. Except for 3 patients who underwent amputation after prosthetic failure, all surviving patients were independent with or without assistive devices at latest follow-up. In patients with advanced metastatic disease, average survival was 7.6 months. No cases of aseptic loosening or implant breakage were observed in patients followed up for 2 years or more. Treatment after tumor resection with a limb salvage prosthetic reconstruction has shown good functional outcomes with an acceptable complication rate. This modality, therefore, offers patients a more favorable functional outcome with a more energy-efficient gait when compared with limb amputation.

Adolescent↗
PubMed1998

Alterations in tau phosphorylation in rat and human neocortical brain slices following hypoxia and glucose deprivation.

Tau is a microtubule-associated protein which is regulated by phosphorylation. Highly phosphorylated tau does not bind microtubules and is the main component of the paired helical filaments seen in Alzheimer's and related neurodegenerative diseases. Recent reports suggested that patterns of tau phosphorylation changed following ischemia and/or reperfusion in vivo. We used an in vitro model employing rat and human neocortical slices to investigate changes in tau phosphorylation which accompany oxygen and glucose deprivation. Western blotting with polyclonal and phosphorylation-sensitive Tau-1 monoclonal antisera was used to monitor changes in tau which accompanied conditions of oxygen and glucose deprivation and reestablishment of these nutrients. In vitro hypoglycemia/hypoxia caused tau to undergo significant dephosphorylation in both rat and human neocortical slices after 30 and 60 min of deprivation. This dephosphorylation was confirmed using immunoprecipitation experiments after radiolabeling tau and other proteins with 32Pi. Okadaic acid, a phosphatase inhibitor, was able to prevent tau dephosphorylation in both control and ischemic slices. Lubeluzole, a benzothiazole derivative with in vivo neuroprotective activity, did not significantly alter patterns of tau phosphorylation. Restoration of oxygen and glucose following varied periods of in vitro hypoxia/hypoglycemia (15-60 min) led to an apparent recovery in phosphorylated tau. These data suggest that tau undergoes a rapid, but reversible dephosphorylation following brief periods of in vitro hypoxia/hypoglycemia in brain slices and that changes in tau phosphorylation help determine the extent of recovery following oxygen and glucose deprivation.

Animals↗
PubMed1996

Microtubule assembly competence analysis of freshly-biopsied human tau, dephosphorylated tau, and Alzheimer tau.

Phosphorylation of the microtubule-associated protein tau regulates its binding to microtubules; highly phosphorylated tau is also a prime component of paired helical filaments (PHFs) of Alzheimer's disease (AD). Tau from freshly biopsied human, monkey, and rat brain share similar electrophoretic mobility patterns and overlapping phosphorylated epitopes when compared to AD tau isolated from AD brain. We compared the microtubule reassembly competence of fresh isolates of phosphorylated tau to that of maximally dephosphorylated tau and tau from AD brain. A rapid procedure was developed which permitted the enrichment of phosphorylated and dephosphorylated tau from human biopsies in the absence of protein kinase and phosphatase activity. Microtubule assembly assays, using a spectrophotometric measure and purified bovine brain tubulin, were used to correlate assembly competence with states of tau electrophoretic mobility. Maximally dephosphorylated human biopsy-derived tau and monkey tau were assembly competent; tau from AD brain was virtually unable to direct microtubule assembly. Unmodified, biopsy-derived tau from non-AD brain was intermediate in assembly competence relative to AD tau and dephosphorylated tau. Several lines of evidence were used to correlate phosphorylation states of tau with microtubule assembly. First, in vitro dephosphorylation of human biopsy-derived tau with either PP2A or PP2B alone or in combination led to increasing assembly competence as the electrophoretic mobility of tau increased. Second, addition of the protein phosphatase inhibitor okadaic acid (10 microM) to brain-slice preparations slowed electrophoretic mobility of tau and decreased binding competence. We suggest that tau derived from freshly-biopsied brain exists in a range of phosphorylated states, and that dephosphorylation by PP2A and/or PP2B increases microtubule assembly competence.

Alzheimer Disease↗
PubMed1996

Cervical spinal epidural haematoma: the double jeopardy.

Spontaneous spinal epidural haematoma is an unusual but well recognized cause of compressive myelopathy or cauda equina syndrome. Radicular pain is one of the earliest symptoms and a hallmark of spontaneous spinal epidural haematoma, as in the case of cervical spondylosis and disc prolapse. Should an epidural haematoma be located in the cervical spine, the resultant cervical radicular pain may sometimes be erroneously attributed to a cardiac cause, especially in the setting of pre-existing cardiac disease. The error in diagnosis can lead to another pitfall, the addition of heparin. If the etiology of the pain is a cervical epidural haematoma this can have grave consequences. Moreover, patients with cardiac ischemia who are treated with anticoagulants may rarely develop a cervical epidural haematoma. The resulting radicular pain can overlap with cardiac pain and escape recognition. Symptoms of neck and upper extremity pain with bilateral signs of myelopathy with a sensory level should lead to a suspicion of acute cervical cord compression. The addition of heparin can only compound the disastrous consequence of a rapidly expanding spinal epidural haematoma. The following cases illustrate this diagnostic and therapeutic conundrum.

Aged↗
PubMed1995

Tau phosphorylation in brain slices: pharmacological evidence for convergent effects of protein phosphatases on tau and mitogen-activated protein kinase.

Tau is a neuron-specific, microtubule-associated protein that forms paired helical filaments (PHFs) of Alzheimer's disease when aberrantly phosphorylated. We have attempted to elucidate the protein kinases and phosphatases that regulate tau phosphorylation. Incubation of rat, human, and rhesus monkey temporal neocortex slices with the phosphatase inhibitor okadaic acid induced epitopes of tau similar to those found in PHFs. Okadaic acid (1-20 microM) induced variant forms of tau at 60-68 kDa, which were recognized by the monoclonal antibodies Alz-50 (in humans only) and 5E2 and two polyclonal antipeptide antisera, OK-1 and OK-2. The phosphorylation-sensitive monoclonal antibody Tau-1 failed to recognize the slowest mobility forms of tau after okadaic acid treatment. FK-520 (1-10 microM), a potent inhibitor of calcineurin activity, was tested in brain slices and found not to alter tau mobility. However, combinations of FK-520 (5 microM) and okadaic acid (100 nM) caused tau mobility shifts similar to those seen after 10 microM okadaic acid treatment; similar results were seen using the calcineurin-selective inhibitor cypermethrin. Treatment of human slices with 10 microM okadaic acid decreased both protein phosphatase 2A and calcineurin activity; FK-520 inhibited only protein phosphatase 2B activity. A proposed tau-directed kinase, 42-kDa mitogen-activated protein kinase (p42mapk), was activated by okadaic acid (> 100 nM) but not FK-520 (5 microM). Nerve growth factor (100 ng/ml) activated p42mapk, particularly when used in combination with 100 nM okadaic acid; changes in tau mobility were seen when this kinase was activated. Forskolin (2 microM) antagonized the effects of nerve growth factor on both p42mapk activity and tau phosphorylation; forskolin alone had little effect on PHF-like tau formation induced by phosphatase inhibitors. These results outline complex interactions between tau-directed protein kinases and protein phosphatases and suggest potential sites for therapeutic intervention.

Amino Acid Sequence↗
PubMed1994

Lectures by neurosurgery and neurology faculty at U.S. medical schools.

The lecture activity of neurology and neurosurgery faculty at allopathic medical schools during the academic years 1985-1986 through 1987-1988 was surveyed. Lectures were categorized into three combinations for analysis: first- and second-year basic science, first- and second-year clinical, and third- and fourth-year clinical lectures. Both faculties delivered more hours of clinical than basic science lectures, and this held true at most schools. Neurology provided lectures at more schools in each of these categories, as well as offering more hours of lecture per student (school medians: 11.5, 18.0, 13.8) than did neurosurgery (school medians: 6.0, 5.5, 8.0). However, neurology faculty number two-and-a-half times neurosurgery faculty. Lectures given per teaching neurology faculty member (12.2) averaged approximately the same as per teaching neurosurgery faculty member (11.5). Increased exposure to the lectures of neurology or neurosurgery faculty did not increase subsequent student enrollment in a first clinical clerkship in that discipline when students had a choice of clerkships.

Clinical Clerkship↗
PubMed1994

Tau phosphorylation in human, primate, and rat brain: evidence that a pool of tau is highly phosphorylated in vivo and is rapidly dephosphorylated in vitro.

The extent of tau phosphorylation is thought to regulate the binding of tau to microtubules: Highly phosphorylated tau does not bind to tubules, whereas dephosphorylated tau can bind to microtubules. It is interesting that the extent of tau phosphorylation in vivo has not been accurately determined. Tau was rapidly isolated from human temporal neocortex and hippocampus, rhesus monkey temporal neocortex, and rat temporal neocortex and hippocampus under conditions that minimized dephosphorylation. In brain slices, we observed that tau isolated under such conditions largely existed in several phosphorylated states, including a pool that was highly phosphorylated; this was determined using epitope-specific monoclonal and polyclonal antibodies. This highly phosphorylated tau was dephosphorylated during a 120-min time course in vitro, presumably as a result of neuronal phosphatase activity. The slow-mobility forms of tau were shifted to faster-mobility forms following in vitro incubation with alkaline phosphatase. Laser densitometry was used to estimate the percent of tau in slow-mobility, highly phosphorylated forms. Approximately 25% of immunoreactive tau was present as slow-mobility (66- and 68-kDa) forms of tau. The percentage of immunoreactive tau in faster-mobility pools (42-54 kDa) increased in proportion to the decrease in content of 66-68-kDa tau as a function of neuronal phosphatases or alkaline phosphatase treatment. These data suggest that the turnover of phosphorylated sites on tau is rapid and depends on neuronal phosphatases. Furthermore, tau is highly phosphorylated in normal-appearing human, primate, and rodent brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaline Phosphatase↗
PubMed1993

Okadaic acid induces hyperphosphorylated forms of tau protein in human brain slices.

Hyperphosphorylated forms of the microtubule-associated protein tau are components of the paired helical filaments (PHFs) seen in patients with Alzheimer's disease. Slices of human lateral temporal cortex were obtained from tissues removed incidental to resections for intractable hippocampal epilepsy. Tau phosphorylation in temporal lobe slices was determined using mobility shifts after sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunodetection with the monoclonal antibodies Alz-50, 5E2, and Tau-1. The results indicate that tau phosphorylation was altered in a dose-dependent manner by the phosphatase inhibitor okadaic acid, but not by N-methyl-D-aspartate, quisqualate, or kainate. The slowest mobility forms of tau, termed "PHF-like tau," produced by okadaic acid treatment were dephosphorylated by purified protein phosphatase 2B (calcineurin). Formation of PHF-like tau peptides was blocked by KN-62, 1[N,O-bis(1,5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazi ne, an inhibitor of Ca2+/calmodulin-dependent protein kinase II. The protein kinase inhibitor staurosporine also prevented formation of PHF-like tau. These data suggest that phosphorylation of tau is regulated by Ca(2+)-dependent protein kinases and okadaic acid-sensitive protein phosphatases, alterations of which may be implicated in the pathogenesis of Alzheimer's disease.

Adult↗
PubMed1992

Cutaneous scar at anterior hair line in mother and child with associated frontal bone defect in child.

A large frontal bone defect underlying a "V" shaped scar was noted in a newborn male whose mother had an identical "V" shaped scar at the same location in the anterior hairline. Both had hypertelorism and short palpebral fissures. The mother had no radiographic evidence of skull defect and neither mother nor child had other cutaneous or skeletal anomalies. Cranioplasty was performed on the child using the remaining frontal bones with an excellent cosmetic result. Biopsy performed at operation documented scar tissue extending through the dermis and underlain by thickened dura. Mother and child appear to have a variant form of aplasia cutis congenita, an autosomal dominant trait with wide variation in expression.

Abnormalities, Multiple↗
PubMed1991

Clinical clerkships in neurosurgery and neurology at United States medical schools.

The neurology and neurosurgery clinical clerkship experience (excluding lectures and conferences) of the students in U.S. allopathic medical schools during one of the academic years 1986 to 1987 or 1987 to 1988 was surveyed. Almost all schools have at least some students taking these clerkships. The majority of students (78%) have clinical exposure to neurology, but only a minority (28%) take a neurosurgical clerkship; however, far more schools require their students to take neurology clerkships (54%) than neurosurgical clerkships (12%). A few require that either be taken. Overall, 81% of schools require all students to take at least one of these clerkships. For the most part, students taking a clerkship in either specialty do not do so again. The initial and usually unique exposure averages 3.5 weeks in neurology and 2.4 weeks in neurosurgery. For each specialty, required clerkships tended to be shorter than selective clerkships, which in turn were shorter than elective ones. Furthermore, first clerkships offered in the fourth year, whether they were required, selective, or elective, tended to be longer than the corresponding third-year first clerkships at other schools. Whereas the average length of a first clinical clerkship in neurology is almost as long for schools requiring it (3.4 wk) as for those that offer it as an elective or selective (4.0 wk), required neurosurgical clerkships are much shorter (1.5 wk) than elective or selective rotations (3.1 wk). Schools with residency training programs more frequently required students to a clerkship and, consequently, had greater numbers of students taking a clerkship in the corresponding specialty.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Clerkship↗
PubMed1990

The influence of growth retardation on perinatal hypoxic-ischemic brain damage.

The effect of growth retardation on the extent of brain damage produced by hypoxia-ischemia was assessed in immature rats. Newborn rats were raised in litters of 6 or 14 pups from day 2 to 7. On postnatal day 7, those immature rats raised in litters of 14 weighed 18% less than animals raised in litters of 6 (P less than 0.001). They then were subjected to cerebral hypoxia-ischemia by unilateral common carotid artery ligation followed by 3 h of exposure to 8% oxygen-92% nitrogen at 37 degrees C. Upon return to their dams, all litters were culled to 6 pups. At 30 days of age, the animals underwent perfusion-fixation of their brains under pentobarbital anesthesia. Brain damage was assessed by measuring the length and width of each cerebral hemisphere. The extent of brain damage varied from no difference in the size of the two cerebral hemispheres to marked shrinkage of the hemisphere ipsilateral to the common carotid artery occlusion. The range of brain damage between the well-nourished and poorly nourished animals was comparable. Rank order of the extent of damage demonstrated significantly greater tissue injury in those animals well nourished prior to hypoxia-ischemia (Mann-Whitney U-test; P = 0.003). The results indicate that nutritional deprivation in the immature rat is associated with a decreased rather than increased susceptibility to brain damage arising from hypoxia-ischemia. The findings of the investigation have relevance to the human infant suffering from intrauterine growth retardation (IUGR).

Animals↗
PubMed1989

Hand preferences of rhesus monkeys on differing tasks.

In a replication study, monkeys were tested for hand preference on three differing tasks: simple reaching for food presented on a board, choice of hand during a visual discrimination task and retrieval of food pellets from a row. Both laterality and degree of hand preference correlated significantly on two of the three tasks. Extremely little correlation was found across the other task combinations. Consistency of hand preference was greater within repetitions of a task than between any two tasks. The implication of these findings upon the search for a cerebral dominance underlying hand preference in the monkey is discussed.

Animals↗
PubMed1988

Cerebral glucose utilization after aversive conditioning and during conditioned fear in the rat.

Regional cerebral glucose utilization (rCMRglu) was studied in rats with and without previous aversive conditioning. Four groups of rats were studied. Two groups of rats were aversely conditioned by placing them in a shock chamber (conditioned stimulus) where they received random footshocks. The two remaining groups were placed in the shock chamber but not conditioned. Regional CMRglu and systemic parameters (heart rate, mean arterial blood pressure (MABP), blood gases and pH, plasma catecholamines, and plasma glucose) were measured in unconditioned and conditioned rats in the presence and in the absence of the conditioned stimulus. The changes in rCMRglu described below appeared to be global and not limited to specific regions. Results are as follows: (1) transferring unconditioned rats to the shock chamber had no significant effect on rCMRglu even though the systemic parameters indicated a stress response. It appears that stress capable of inducing changes in heart rate, MABP, and plasma catecholamines is not necessarily accompanied by increases in cerebral glucose utilization. (2) Conditioned rats not exposed to the shock chamber at the time rCMRglu was measured had decreased rates of rCMRglu compared to rats that were not conditioned. Except for plasma epinephrine, which increased after conditioning, systemic parameters were not affected. (3) Conditioned fear, elicited by transferring conditioned rats to the shock chamber, increased rCMRglu when compared to a control group that was conditioned to footshock using the same paradigm but not exposed to the shock chamber at the time rCMRglu was measured. The systemic parameters indicated a stress response in conditioned rats transferred to the shock chamber.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗