Ligand dynamics and protonation preferences of Rh and Ir complexes bearing an almost, but not quite, pendent base.

Pendent nucleophiles are essential partners in the cleavage and formation of bonds with hydrogen (e.g. protonation/deprotonation), but binding of the pendent group to the metal and the potential trapping of complexes in inactive states are a significant problem. The dipyridylmethane-based ligand framework bis(2-pyridyl)-N-pyrrolidinomethane (R,pyrCPy2), bearing a hemilabile pyrrolidine moiety, has been synthesized and complexes of the type [(R,pyrCPy2)M(COD)]X (COD = 1,5-cyclooctadiene) were prepared. The solution-phase ligand dynamics and relative protonation preferences were investigated via1H NMR spectroscopy; although favorable, pendent amine binding does not kinetically inhibit pendent base protonation. Protonation at the metal (with concomitant pyrrolidine binding) has been found to be favorable for Ir, whereas N-protonation is favorable for Rh. DFT calculations predict that the RhIII hydrides have much higher relative acidities than their Ir congeners (ΔpKa ≃ 7-8 in CH2Cl2), and are also more acidic than the strong acid [H(OEt2)2][B(C6F5)4].

Sequential specification of neurons and glia by developmentally regulated extracellular factors.

Cortical progenitor cells give rise to neurons during embryonic development and to glia after birth. While lineage studies indicate that multipotent progenitor cells are capable of generating both neurons and glia, the role of extracellular signals in regulating the sequential differentiation of these cells is poorly understood. To investigate how factors in the developing cortex might influence cell fate, we developed a cortical slice overlay assay in which cortical progenitor cells are cultured over cortical slices from different developmental stages. We find that embryonic cortical progenitors cultured over embryonic cortical slices differentiate into neurons and those cultured over postnatal cortical slices differentiate into glia, suggesting that the fate of embryonic progenitors can be influenced by developmentally regulated signals. In contrast, postnatal progenitor cells differentiate into glial cells when cultured over either embryonic or postnatal cortical slices. Clonal analysis indicates that the postnatal cortex produces a diffusible factor that induces progenitor cells to adopt glial fates at the expense of neuronal fates. The effects of the postnatal cortical signals on glial cell differentiation are mimicked by FGF2 and CNTF, which induce glial fate specification and terminal glial differentiation respectively. These observations indicate that cell fate specification and terminal differentiation can be independently regulated and suggest that the sequential generation of neurons and glia in the cortex is regulated by a developmental increase in gliogenic signals.

The pharmacoeconomics of venlafaxine in depression.

The prevalence of depression and the high costs associated with its management have heightened interest in pharmacoeconomic evaluation of drug treatment, especially the use of selective serotonin reuptake inhibitors (SSRIs) and the serotonin-norepinephrine reuptake inhibitor venlafaxine. A number of studies of venlafaxine in both inpatient and outpatient settings have revealed that extended-release venlafaxine has a lower expected cost than comparable treatment with SSRIs and tricyclic antidepressants (TCAs). When the relative cost effectiveness of immediate-release venlafaxine, SSRIs, and TCAs was assessed in the treatment of major depressive disorder in 10 countries, venlafaxine yielded a lower than expected cost compared with SSRIs and TCAs in all but 1 country. In comparing healthcare expenditures for depressed patients with and without anxiety, there was a pharmacoeconomic benefit to both immediate- or extended-release venlafaxine, regardless of the presence or absence of comorbid anxiety. A review of computerized administrative claims data from 9 US healthcare plans on resource use and the cost of venlafaxine instead of TCAs after switching from an SSRI showed that overall costs did not vary markedly between venlafaxine and TCAs. This led to the conclusion that although therapy with venlafaxine is more costly than TCA therapy, this increase may be offset by lower costs of other medical services. Such findings have enormous potential ramifications for practicing physicians in terms of venlafaxine's superior remission rate, lower likelihood of relapse, loss of fewer patients to adverse events or lack of efficacy, and flexibility in dosing that enables titration to achieve an optimal response.

Putting to use a clinical guideline for treating tobacco dependency.

The issuance last year of the U.S. Public Health Services' clinical guideline for treating tobacco use and dependency offered managed care a tool that could help them achieve the Healthy People 2010 goals of cutting adult smoking rates in half. The authors describe how the guidelines approach this difficult public health issue.

Hearing rehabilitation using the BAHA bone-anchored hearing aid: results in 40 patients.

OBJECTIVE: This study evaluates the U.S. experience with the first 40 patients who have undergone audiologic rehabilitation using the BAHA bone-anchored hearing aid. STUDY DESIGN: This study is a multicenter, nonblinded, retrospective case series. SETTING: Twelve tertiary referral medical centers in the United States. PATIENTS: Eligibility for BAHA implantation included patients with a hearing loss and an inability to tolerate a conventional hearing aid, with bone-conduction pure tone average levels at 60 dB or less at 0.5, 1, 2, and 4 kHz. INTERVENTION: Patients who met audiologic and clinical criteria were implanted with the Bone-Anchored Hearing Aid (BAHA, Entific Corp., Gothenburg, Sweden). MAIN OUTCOME MEASURES: Preoperative air- and bone-conduction thresholds and air-bone gap; postoperative BAHA-aided thresholds; hearing improvement as a result of implantation; implantation complications; and patient satisfaction. RESULTS: The most common indications for implantation included chronic otitis media or draining ears (18 patients) and external auditory canal stenosis or aural atresia (7 patients). Overall, each patient had an average improvement of 32+/-19 dB with the use of the BAHA. Closure of the air-bone gap to within 10 dB of the preoperative bone-conduction thresholds (postoperative BAHA-aided threshold vs. preoperative bone-conduction threshold) occurred in 32 patients (80%), whereas closure to within 5 dB occurred in 24 patients (60%). Twelve patients (30%) demonstrated 'overclosure' of the preoperative bone-conduction threshold of the better hearing ear. Complications were limited to local infection and inflammation at the implant site in three patients, and failure to osseointegrate in one patient. Patient response to the implant was uniformly satisfactory. Only one patient reported dissatisfaction with the device. CONCLUSIONS: The BAHA bone-anchored hearing aid provides a reliable and predictable adjunct for auditory rehabilitation in appropriately selected patients, offering a means of dramatically improving hearing thresholds in patients with conductive or mixed hearing loss who are otherwise unable to benefit from traditional hearing aids.

Temporal and spatial dynamics of human forebrain activity during heat pain: analysis by positron emission tomography.

To learn about the sequence of brain activation patterns during heat pain, we acquired positron emission tomographic (PET) brain scans at different times during repetitive heat stimulation (40 or 50 degrees C; 5-s contact) of each subject's left forearm. Early scans began at the onset of 60 s of stimulation; late scans began after 40 s of stimulation, which continued throughout the 60-s scan period (total stimulus duration 100 s). Each subject (14 normal, right-handed subjects; 10 male, 4 female; ages 18-42) used a visual analog scale to rate the perceived stimulus intensity (0 = no heat, 7 = pain threshold, 10 = barely tolerable pain) after each scan. The 40 degrees C stimulation received an average intensity rating of 2.19 +/- 1.22 (mean +/- SD) and the 50 degrees C an average rating of 8.93 +/- 1.33. During the scan sessions, subjects did not report a difference between early and late scans. To examine the effect of the duration of stimulation specifically, 8 of these subjects rated the perceived intensity of each of 20 sequential 5-s duration contact heat stimuli (40 or 50 degrees C; 100 s of stimulation). We used a graphical method to detect changes in perceived unpleasantness. There was no difference in perceived intensity or unpleasantness during the 40 degrees C stimulation. However, during 50 degrees C stimulation, perceived unpleasantness increased and subjects perceived the last five, but not the second five, stimuli as more intense than the first five stimuli. These psychophysical changes could be mediated by brain structures with increasing activity from early to late PET scans or that are active only during late scans. These structures include the contralateral M1/S1 cortex, bilateral S2 and mid-insular cortex, contralateral VP thalamus, medial ipsilateral thalamus, and the vermis and paravermis of the cerebellum. Structures that are equally active throughout stimulation (contralateral mid-anterior cingulate and premotor cortex) are less likely to mediate these psychophysical changes. Some cortical, but not subcortical, structures showed significant or borderline activation only during the early scans (ipsilateral premotor cortex, contralateral perigenual anterior cingulate, lateral prefrontal, and anterior insular cortex); they may mediate pain-related attentive or anticipatory functions. Overall, the results reveal that 1) the pattern of brain activation and the perception of heat pain both change during repetitive noxious heat stimulation, 2) cortical activity can be detected before subcortical responses appear, and 3) timing the stimulation with respect to the scan period can, together with psychophysical measurements, identify brain structures that are likely to participate in the perception of pain.

A Comparison of the Hybrid III and BioRID II Dummies in Low-Severity, Rear-Impact Sled Tests.

A BioRID II dummy and a Hybrid III dummy, each representative of a midsize adult male, were tested side-by-side in simulated rear-impact sled tests. In all tests the dummies were restrained by 3-point belt systems. The results of 4 test sets conducted at a nominal change in velocity (deltaV) of 16 km/hr are presented and discussed. In three of the test sets, bucket seats were used. The head restraints were placed in the up-position in two of the three test sets and in the down-position in the third set of tests. In the fourth test set, rigid seats without any head restraints were used. While analyzing the BioRID II data, the presence of an axial neck load acting on the head, which bypassed the upper neck load transducer, was discovered in all the reported tests. The implication of this observation is that the axial force and all the moments measured by the BioRID II upper neck load transducer could be erroneous. A second concern with the BioRID II data was the high frequency noise observed, especially on the T1 acceleration response which is used in the NIC calculation. The 18 Hz filter used to process the T1 acceleration data for the NIC calculation attenuated the peak NIC values by 15% as compared to the SAE 180 filtered values. The unmeasured neck loads and high-frequency noise issues need to be resolved before additional BioRID II testing is done. A third concern with the BioRID II is the initial position of its head in the automotive seating posture. It is higher and more forward than that of the 50(th) percentile adult male.

Attention-related, cross-modality modulation of somatosensory neurons in primate ventrobasal (VB) thalamus.

Attention-related modulation (AM) of the somatosensory responses of single neurons has been demonstrated in the cerebral cortex and medullary dorsal horn, but not in the ventrobasal thalamus. The somatically evoked activity was recorded of single units in the ventral posterior lateral thalamus (VPL) of awake monkeys while they detected the termination of task-relevant somatic or visual stimuli. Eighteen of 56 somatically responsive VPL neurons are reported that were recorded for enough time for a complete analysis of their responses during both the visual and somatic attention tasks. All neurons were spontaneously active and responded either to innocuous cutaneous (13/18) or deep (5/18) stimuli. Seven neurons (7/18, 38.8%) showed AM of somatosensory responsiveness. Two cells (2/7, 28.6%) showed AM only during the visual task, two others (2/7, 28.6%) only during the somatosensory task, and three cells (3/7, 42.8%) showed AM during both tasks. All five cells showing AM during the somatosensory task had enhanced responses to the task-relevant somatic stimulus. In contrast, the somatosensory responses of all five cells showing AM during the visual task were reduced. It is concluded that selective attention is associated with a modality specific modulation of the somatosensory responses of a sub-population of neurons within the primate VPL nucleus.

Selective opiate modulation of nociceptive processing in the human brain.

Fentanyl, a mu-opioid receptor agonist, produces analgesia while leaving vibrotactile sensation intact. We used positron emission tomography (PET) to study the mechanisms mediating this specific effect in healthy, right-handed human males (ages 18-28 yr). Subjects received either painful cold (n = 11) or painless vibratory (n = 9) stimulation before and after the intravenous injection of fentanyl (1.5 microgram/kg) or placebo (saline). Compared with cool water (29 degrees C), immersion of the hand in ice water (1 degrees C) is painful and produces highly significant increases in regional cerebral blood flow (rCBF) within the contralateral second somatosensory (S2) and insular cortex, bilaterally in the thalamus and cerebellum, and medially in the cerebellar vermis. Responses just below the statistical threshold (3.5 < Z < 4.0) are seen in the contralateral anterior cingulate, ipsilateral insular cortex, and dorsal medial midbrain. The contralateral primary sensory cortex (S1) shows a trend of activation. Except for slight changes in intensity, this pattern is unchanged following a saline placebo injection. Fentanyl reduces the average visual analogue scale ratings of perceived pain intensity (47%) and unpleasantness (50%), reduces pain-related cardioacceleration, and has positive hedonic effects. After fentanyl, but not placebo, all cortical and subcortical responses to noxious cold are greatly reduced. Subtraction analysis [(innocuous water + fentanyl) - (innocuous water + no injection)] shows that fentanyl alone increases rCBF in the anterior cingulate cortex, particularly in the perigenual region. Vibration (compared with mock vibration) evokes highly significant rCBF responses in the contralateral S1 cortex in the baseline (no injection) and placebo conditions; borderline responses (3.5 < Z < 4. 0) are detected also in the contralateral thalamus. Fentanyl has no effect on the perceived intensity or unpleasantness of vibratory stimulation, which continues to activate contralateral S1. Fentanyl alone [(mock vibration + fentanyl) - (mock vibration + no injection)] again produces highly significant activation of the perigenual and mid-anterior cingulate cortex. A specific comparison of volumes of interest, developed from activation peaks in the baseline condition (no injection), shows that fentanyl strongly attenuates both the contralateral thalamic and S1 cortical responses to noxious cold stimulation (P < 0.048 and 0.007, respectively) but fails to affect significantly these responses to vibrotactile stimulation (P > 0.26 and 0.91, respectively). In addition, fentanyl, compared with placebo, produces a unique activation of the mid-anterior cingulate cortex during fentanyl analgesia, suggesting that this region of the cingulate cortex participates actively in mediating opioid analgesia. The results are consistent with a selective, fentanyl-mediated suppression of nociceptive spinothalamic transmission to the forebrain. This effect could be implemented directly at the spinal level, indirectly through cingulate corticofugal pathways, or by a combination of both mechanisms.

Semaphorin 3A is a chemoattractant for cortical apical dendrites.

The apical dendrites of pyramidal neurons integrate inputs from various cortical layers and are central to information processing. Here we show that the growth of apical dendrites towards the pial surface is regulated by a diffusible chemoattractant present at high levels near the marginal zone. A major component of this signal is semaphorin 3A (Sema3A), which was previously characterized as a chemorepellant for cortical axons. Soluble guanylate cyclase is asymmetrically localized to the developing apical dendrite, and is required for the chemoattractive effect of Sema3A. Thus the asymmetric localization of soluble guanylate cyclase confers distinct Sema3A responses to axons and dendrites. These observations reveal a mechanism by which a single chemotropic signal can pattern both axons and dendrites during development.

Chondromyxoid fibroma of the nasal septum: a case report emphasizing clinical correlation.

Chondromyxoid fibromas are uncommon tumors most often seen in long bones of adolescent and young males. Involvement of craniofacial bones is extremely unusual, with sporadic case reports described in the literature. We describe the first case of chondromyxoid fibroma arising in the nasal septum with local destruction and expansile growth into the ethmoid bone and inferior turbinate in a 60-year-old female. The fortuitous discovery of this otherwise asymptomatic lesion and its follow-up are detailed. The literature is reviewed and salient clinical, radiographic, and pathologic correlative findings are emphasized.

Chronic, selective forebrain responses to excitotoxic dorsal horn injury.

Intraspinal injection of the AMPA/metabotropic receptor agonist quisqualic acid (QUIS) results in excitotoxic injury which develops pathological characteristics similar to those associated with ischemic and traumatic spinal cord injury (SCI) (R. P. Yezierski et al., 1998, Pain 75: 141-155; R. P. Yezierski et al., 1993, J. Neurotrauma 10: 445-456). Since spinal injury can lead to partial or complete deafferentation of ascending supraspinal structures, it is likely that secondary to the disruption of spinal pathways these regions could undergo significant reorganization. Recently, T. J. Morrow et al. (Pain 75: 355-365) showed that autoradiographic estimates of regional cerebral blood flow (rCBF) can be used to simultaneously identify alterations in the activation of multiple forebrain structures responsive to noxious formalin stimulation. Accordingly, we examined whether excitotoxic SCI produced alterations in the activation of supraspinal structures using rCBF as a marker of neuronal activity. Twenty-four to 41 days after unilateral injection of QUIS into the T12 to L3 spinal segments, we found significant increases in the activation of 7 of 22 supraspinal structures examined. As compared to controls, unstimulated SCI rats exhibited a significant bilateral increase in rCBF within the arcuate nucleus (ARC), the hindlimb region of S1 cortex (HL), parietal cortex (PAR), and the thalamic posterior (PO), ventral lateral (VL), ventral posterior lateral (VPL), and ventral posterior medial (VPM) nuclei. All structures showing significantly altered rCBF are associated with the processing of somatosensory information. These changes constitute remote responses to injury and suggest that widespread functional changes occur within cortical and subcortical regions following injury to the spinal cord.

Bilateral behavioral and regional cerebral blood flow changes during painful peripheral mononeuropathy in the rat.

A unilateral chronic constriction injury (CCI) of the sciatic nerve produced bilateral effects in both pain related behaviors and in the pattern of forebrain activation. All CCI animals exhibited spontaneous pain-related behaviors as well as bilateral hyperalgesia and allodynia after CCI. Further, we identified changes in baseline (unstimulated) forebrain activation patterns 2 weeks following CCI by measuring regional cerebral blood flow (rCBF). Compared to controls, CCI consistently produced detectable, well-localized and typically bilateral increases in rCBF within multiple forebrain structures in unstimulated animals. For example, the hindlimb region of somatosensory cortex was significantly activated (22%) as well as multiple thalamc nuclei, including the ventral medial (8%), ventral posterior lateral (10%) and the posterior (9%) nuclear groups. In addition, several forebrain regions considered to be part of the limbic system showed pain-induced changes in rCBF, including the anterior dorsal nucleus of the thalamus (23%), cingulate cortex (18%), retrosplenial cortex (30%), habenular complex (53%), interpeduncular nucleus (45%) and the paraventricular nucleus of the hypothalamus (30%). Our results suggest that bilateral somatosensory and limbic forebrain structures participate in the neural mechanisms of prolonged persistent pain produced by a unilateral injury.

Roundtable discussion: Part I--Epidemiologic, demographic, and treatment challenges in hypertension.

Hypertension is one of the most pervasive medical disorders in this country. As the nation's population ages, the number of patients with hypertension can be expected to rise substantially. On December 9, 1999, a panel of managed care medical directors, pharmacy directors, clinicians, and health economists convened in Irvine, Texas to discuss aspects of hypertension management and economic analysis. This roundtable is presented in three parts, including (1) a summary of the challenges of hypertension management from the point of view of the clinician, (2) the introduction of a pharmacoeconomic model of hypertension management, and (3) a discussion of how health plans approach this insidious disorder.

Roundtable discussion: Part II--Development of a pharmacoeconomic model in hypertension.

Antihypertensive medications are targeted by most health plans as a major cost center. However, the efficacy of these medications, their side effects, and their resulting ability to prevent serious long-term complications must be factored into the value equation. To illustrate the possible economic effects of a single antihypertensive agent's inclusion on a health plan's drug formulary, an innovative pharmacoeconomic model was developed. In this portion of the roundtable, the design, results, and caveats of this model are discussed.

Roundtable discussion: Part III--Hypertension management in health plans.

In the final section of the roundtable discussion, participants describe how their individual managed care plans approach hypertension from the standpoints of disease management targeting, strategies to combat noncompliance, and how these plans utilize pharmacoeconomic information in drug formulary decision making.

Management of menopause: a new HEDIS measure and an opportunity for health plans.

A new measurement was added to the 2000 Health Plan Employer Data and Information Set (HEDIS) in June. The "management of menopause" measure allows health plans an opportunity to better serve a segment of the population that has traditionally been overlooked. The authors describe in detail the new HEDIS measurement criteria and how they represent an opportunity for health plans to better meet the needs of their perimenopausal enrollees.

Pro-B-cell-specific transcription and proapoptotic function of protein kinase Ceta.

Using a subtractive cloning scheme on cDNA prepared from primary pro-B and pre-B cells, we identified several genes whose products regulate apoptosis. We further characterized one of these genes, encoding protein kinase Ceta (PKCeta). PKCeta transcripts were readily detected in pro-B cells but were absent in pre-B cells. Although both a full-length and a truncated form of PKCeta were detectable in bone marrow pro-B cells, transition to the pre-B-cell stage was associated with increased relative levels of truncated PKCeta. We found that PKCeta is proteolyzed in apoptotic lymphocytes, generating a kinase-active fragment identical to the truncated form which is capable of inducing apoptosis when expressed in a pro-B cell line. Caspase-3 can generate an identical PKCeta cleavage product in vitro, and caspase inhibitors prevent the generation of this product during apoptosis in transfected cell lines. Inducible overexpression of either the full-length or truncated form of PKCeta results in cell cycle arrest at the G(1)/S transition. These results suggest that the expression and proteolytic activation of PKCeta play an important role in the regulation of cell division and cell death during early B-cell development.

Gender differences in pain perception and patterns of cerebral activation during noxious heat stimulation in humans.

The purpose of the present study was to determine whether gender differences exist in the forebrain cerebral activation patterns of the brain during pain perception. Accordingly, positron emission tomography (PET) with intravenous injection of H2(15)O was used to detect increases in regional cerebral blood flow (rCBF) in normal right-handed male and female subjects as they discriminated differences in the intensity of innocuous and noxious heat stimuli applied to the left forearm. Each subject was instructed in magnitude estimation based on a scale for which 0 indicated 'no heat sensation'; 7, 'just barely painful' and 10, 'just barely tolerable'. Thermal stimuli were 40 degrees C or 50 degrees C heat, applied with a thermode as repetitive 5-s contacts to the volar forearm. Both male and female subjects rated the 40 degrees C stimuli as warm but not painful and the 50 degrees C stimuli as painful but females rated the 50 degrees C stimuli as significantly more intense than did the males (P=0.0052). Both genders showed a bilateral activation of premotor cortex in addition to the activation of a number of contralateral structures, including the posterior insula, anterior cingulate cortex and the cerebellar vermis, during heat pain. However, females had significantly greater activation of the contralateral prefrontal cortex when compared to the males by direct image subtraction. Volume of interest comparison (t-statistic) also suggested greater activation of the contralateral insula and thalamus in the females (P < 0.05). These pain-related differences in brain activation may be attributed to gender, perceived pain intensity, or to both factors.