Evidence for increased T cell turnover and decreased thymic output in HIV infection.

The effects of HIV infection upon the thymus and peripheral T cell turnover have been implicated in the pathogenesis of AIDS. In this study, we investigated whether decreased thymic output, increased T cell proliferation, or both can occur in HIV infection. We measured peripheral blood levels of TCR rearrangement excision circles (TREC) and parameters of cell proliferation, including Ki67 expression and ex vivo bromodeoxyuridine incorporation in 22 individuals with early untreated HIV disease and in 15 HIV-infected individuals undergoing temporary interruption of therapy. We found an inverse association between increased T cell proliferation with rapid viral recrudescence and a decrease in TREC levels. However, during early HIV infection, we found that CD45RO-CD27high (naive) CD4+ T cell proliferation did not increase, despite a loss of TREC within naive CD4+ T cells. A possible explanation for this is that decreased thymic output occurs in HIV-infected humans. This suggests that the loss of TREC during HIV infection can arise from a combination of increased T cell proliferation and decreased thymic output, and that both mechanisms can contribute to the perturbations in T cell homeostasis that underlie the pathogenesis of AIDS.

Public roles for the medical profession in the United States: beyond theories of decline and fall.

The future role of national medical organizations as a moral voice in health policymaking in the United States deserves attention from both scholarly and strategic perspectives. Arguments for strengthening the public roles of organized professionalism include its long (if neglected) history of public service. Scholarship of the past 40 years has emphasized the decline of a profession imbued with self-interest, together with associated theories of organizational conflict. Through new concepts and language, a different version of organized medicine from that of the past might be invented for the future--one that draws on multiple medical organizations, encourages more effective cooperation with other health care groups, and builds on traditional professional agendas through adaptation and extension.

Activation of progelatinase A by mammalian legumain, a recently discovered cysteine proteinase.

The activation of progelatinase A to gelatinase A requires cleavage of an asparaginyl bond to form the N-terminus of the mature enzyme. We have asked whether the activation can be mediated by legumain, the recently discovered lysosomal cysteine proteinase that is specific for hydrolysis of asparaginyl bonds. Addition of purified legumain to the concentrated conditioned medium from HT1080 cell culture that contained both progelatinases A and B caused the conversion of the 72 kDa progelatinase A to the 62 kDa form. The progelatinase B in the medium was unaffected. Incubation of recombinant progelatinase A with legumain resulted in an almost instantaneous activation as judged by the fluorometric assay with a specific gelatinase A substrate, Mca-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2. Legumain also activated progelatinase A when it was in complex with TIMP-2. Zymographic analysis and N-terminal sequencing revealed that legumain cleaved the 72 kDa progelatinase A at the bonds between Asn109-Tyr110 or Asn111-Phe112 to produce the 62 kDa mature enzyme, and that further cleavage at Asn430 also occurred to generate a 36 kDa active form. More 62 kDa gelatinase A was detected in cultures of C13 cells that over-expressed legumain than in those of the control HEK293 cells. We conclude that legumain is clearly capable of processing progelatinase A to the active enzyme in vitro and in cultured cells.

What constitutes an effective but safe initial dose of lidocaine to test a thoracic epidural catheter?

To investigate the effects of age and dose on the spread of thoracic epidural anesthesia, we placed thoracic epidural catheters in 50 surgical patients divided into groups by age (Group I [young], 18-51 yr; Group II [old], 56-80 yr) and randomly assigned patients to receive either 5 mL (A) or 9 mL (B) of 2% lidocaine (plain) injected via the epidural catheter. Hemodynamic variables were measured (heart rate, mean arterial blood pressure, noninvasive impedance cardiac index) at baseline and every 5 min for 30 min. Detectable blockade occurred within 8 min after injection of 3 + 2 mL or 3 + 6 mL in 48 of 50 patients. Maximum spread of analgesia to pinprick occurred 15-23 min after completion of local anesthetic injection and was significantly different between age and volume groups by two-way analysis of variance (Group IA [young 5], 10.9 +/- 4.0 dermatomes; Group IIB [young 9], 13.9 +/- 4.5 dermatomes; Group IIA [old 5], 14.1 +/- 5.6 dermatomes; and Group IIB [old 9], 17.4 +/- 5.1 dermatomes). Minor decreases in mean arterial blood pressure (8%-17%) and heart rate (4%-11%) were noted. Two patients in the Old 9 group required IV ephedrine or ephedrine/atropine to treat hypotension and bradycardia. We conclude that given the rapid onset (3-8 min), extensive spread (11-14 dermatomal segments), and consistent hemodynamic stability, thoracic epidural anesthesia should be initiated with lidocaine 100 mg (5 mL 2% lidocaine) to establish proper location of the catheter in the epidural space in both younger and older patients.

Reversal of lidocaine with epinephrine epidural anesthesia using epidural saline washout.

BACKGROUND AND OBJECTIVES: Prolonged motor and sensory block following epidural anesthesia can be associated with extended postoperative care unit stays and patient dissatisfaction. Previous studies have demonstrated a more rapid motor recovery following the administration of epidural crystalloids in patients who had received plain bupivacaine and lidocaine epidural anesthesia. However, epinephrine is commonly added to local anesthetics to improve the quality and prolong the duration of the epidural block. The objective of this study was to determine the relationship of 0.9% NaCl epidural catheter flush volume (i.e., washout) to the recovery of motor and sensory block in patients undergoing 2% lidocaine with epinephrine epidural anesthesia. METHODS: A prospective, randomized, double-blind study design was utilized. Thirty-three subjects scheduled for elective gynecologic or obstetrical surgical procedures underwent epidural anesthesia using 2% lidocaine with epinephrine (1:200,000). A T4 dermatome level of analgesia, determined by toothpick prick, was maintained intraoperatively. Following surgery, subjects were randomized to 1 of 3 treatment groups. Group 1 (control, n = 11) received no epidural 0.9% NaCl (normal saline [NS]) postoperatively. Group 2 (15 mL NS x 1, n = 10) received an epidural bolus of 15 mL NS. Group 3 (15 mL NS x 2, n = 12) received an epidural bolus of 15 mL NS postoperatively and a second 15-mL NS bolus 15 minutes later. Assessment of motor and sensory block was performed at 15-minute intervals until complete motor and sensory recovery. RESULTS: Times to partial and full motor and sensory recovery were significantly faster in the epidural NS groups than in the control group. Full motor recovery was more rapid in subjects receiving two 15-mL NS epidural NS boluses (30 mL total) compared with those receiving a single 15-mL NS bolus (108 +/- 9 min v 136 +/- 13 min) and significantly faster than control group subjects (153 +/- 14 min). Both NS x 1 and NS x 2 epidural bolus groups experienced significantly reduced times to complete sensory recovery when compared with the control group (NS x 1 = 154 +/- 13 min, NS x 2 = 153 +/- 9 min, control 195 +/- 14 min). CONCLUSIONS: A more rapid recovery of motor and sensory block in patients undergoing 2% lidocaine with epinephrine epidural anesthesia can be achieved with the use of 30 mL NS epidural washout. Reg Anesth Pain Med 2001;26:246-251.

The Americanization of family medicine: contradictions, challenges, and change, 1969-2000.

Family practice became the 20th medical specialty in 1969, identified by its leaders as a harbinger of health care reform, as well as practice excellence, and with expectations of continuing government support of its purpose and role. Since that time, the cultural and political environments have changed significantly in some ways, and not changed in others as initially expected, thus challenging the new specialty with pressures for reinvention with respect to its identity, function, and prestige. The most important impediment to a clear-cut role for family practice has been the lack of a formal administrative structure for primary care practice on a nationwide basis in the United States. Differentiation of the field from all other parts of medicine was also difficult because of the identification of family practice with the professional accoutrements of a specialty, parallel to other specialist fields. Family practice moved from an outsider role in medicine to a position of entrenchment in the medical establishment, including hospitals and academic medical centers. And, family practice became one of several overlapping and competing primary care fields. The role of family practice in US culture is now less clear than the potential role envisioned for it in 1969. Its multiple and not always well-defined roles in medicine may make it difficult to establish a clear identity for the specialty in the future. If it is to be successful, family practice must develop allies and work aggressively to establish its role in primary care. It must also work to institute primary care in the US medical system and act politically (as in the 1960s), taking advantage of current cultural trends, notably the information revolution and the growth of biomedical research.

Impact of HIV-1 infection and highly active antiretroviral therapy on the kinetics of CD4+ and CD8+ T cell turnover in HIV-infected patients.

To evaluate the effects of HIV infection on T cell turnover, we examined levels of DNA synthesis in lymph node and peripheral blood mononuclear cell subsets by using ex vivo labeling with BrdUrd. Compared with healthy controls (n = 67), HIV-infected patients (n = 57) had significant increases in the number and fraction of dividing CD4(+) and CD8(+) T cells. Higher percentages of dividing CD4(+) and CD8(+) T cells were noted in patients with the higher viral burdens. No direct correlation was noted between rates of T cell turnover and CD4(+) T cell counts. Marked reductions in CD4(+) and CD8(+) T cell proliferation were seen in 11/11 patients 1-12 weeks after initiation of highly active antiretroviral therapy (HAART). These reductions persisted for the length of the study (16-72 weeks). Decreases in naive T cell proliferation correlated with increases in the levels of T cell receptor rearrangement excision circles. Division of CD4(+) and CD8(+) T cells increased dramatically in association with rapid increases in HIV-1 viral loads in 9/9 patients 5 weeks after termination of HAART and declined to pre-HAART-termination levels 8 weeks after reinitiation of therapy. These data are consistent with the hypothesis that HIV-1 infection induces a viral burden-related, global activation of the immune system, leading to increases in lymphocyte proliferation.

Postherpetic neuralgia in the cancer patient.

Postherpetic neuralgia (PHN) is the most common and devastating complication of acute herpes zoster (HZ). HZ occurs more frequently in the patient with human immunodeficiency virus (HIV) and with certain leukemias and lymphomas. PHN occurs more frequently in the elderly, in patients with severe pain in the acute stage, and in patients with lesions in the ophthalmic branch of the trigeminal nerve. Pain from PHN is often debilitating and difficult to treat. A wide variety of therapeutic approaches have been advocated over the years, but most are not very effective. Early aggressive treatment of HZ with antiviral drugs may be the most important step in prophylaxis against PHN. This article reviews the current knowledge of the pathogenesis and treatment of PHN.

Is succinylcholine after pretreatment with d-tubocurarine and lidocaine contraindicated for outpatient anesthesia?

UNLABELLED: Because succinylcholine has obvious advantages for facilitating endotracheal intubation in the ambulatory setting (e.g., low cost, fast onset, and no need for reversal of neuromuscular block), it is important to determine whether this muscle relaxant is indeed associated with an increased incidence of postoperative myalgias, compared with alternative but more expensive nondepolarizing muscle relaxants. We studied 119 outpatients undergoing endoscopic nasal sinus surgery or septoplasty. The anesthetic technique consisted of propofol/lidocaine for induction, followed by isoflurane/nitrous oxide/oxygen for maintenance. Oral tracheal intubation was performed by using a fiberscope. Patients were randomly assigned to one of two muscle relaxant groups. Group 1 patients received d-tubocurarine 3 mg followed by succinylcholine 1.5 mg/kg. Group 2 patients received mivacurium 0.2 mg/kg. After recovery from anesthesia, patients were asked whether they had any muscle pain and/or stiffness. Pain was categorized by location and quantified by using a verbal scale (from 0 to 10). Analgesic usage and myalgias limiting ambulation were recorded. After discharge from the ambulatory surgery unit, patients were contacted by telephone on Postoperative Day 1. If patients complained of myalgias, they were contacted by telephone on Days 2 and 3. Only one patient (in the mivacurium-treated group) reported myalgia as a limiting factor in ambulation or resumption of normal activity. There were no differences between groups with respect to the incidence (21% in the succinylcholine-treated group and 18% in the mivacurium-treated group), location, or severity of myalgia. In conclusion, succinylcholine (preceded by pretreatment with d-tubocurarine and lidocaine) is not associated with an increased incidence of myalgias, compared with mivacurium, when used to facilitate tracheal intubation in patients undergoing ambulatory nasal surgery. IMPLICATIONS: The results of this study show that the frequency of muscle pains after surgery in outpatients is approximately 20%, regardless of whether succinylcholine (after precurarization) or mivacurium is used to assist in insertion of the breathing tube.

Routes of opioid analgesic therapy in the management of cancer pain.

BACKGROUND: The availability of various routes of administration of opioid analgesics can be confusing when determining an appropriate, efficacious, and cost-effective regimen to manage cancer pain. METHODS: The indications, contraindications, and pharmacokinetic properties of oral, intravenous, subcutaneous, transdermal, transmucosal, rectal, and perispinal routes of opioid administration are reviewed. RESULTS: To determine the most efficacious, cost-effective, and user-friendly option to manage cancer pain, several factors must be considered: the ability of the patient to use a specific type of delivery system, the efficacy of that system to deliver acceptable analgesia, the ease of use for the patient and family, the potential or actual complications associated with that system, and the cost. CONCLUSIONS: Administering opioids to manage cancer pain requires knowledge of potency relative to morphine and bioavailability of the route chosen. Changes in the route, dosage, or opioid used should be accompanied with close patient follow-up.

A collaborative regional ocular anesthesia training program: successes and failures.

STUDY OBJECTIVE: To describe a collaborative effort of the departments of ophthalmology and anesthesiology to teach anesthesiology residents regional ocular anesthesia; to detect any differences in positive or negative outcomes after blocks performed by anesthesiology residents versus blocks performed by ophthalmology residents. DESIGN: Prospective descriptive, study. SETTING: Outpatient surgery in a university-affiliated veterans affairs hospital. PATIENTS: 614 patients requiring elective ocular surgery. INTERVENTIONS: Outcomes from patients who underwent regional anesthesia performed by ophthalmology residents were compared to outcomes from patients who received anesthesia from anesthesiology residents. MEASUREMENTS AND MAIN RESULTS: A detailed description of the collaborative teaching program in ocular anesthesia is presented. Ophthalmology residents performed the majority of regional ocular blocks (87% vs. 13%). There was no statistical difference in the incidence of negative outcomes, such as retrobulbar hemorrhage, between ophthalmology residents and anesthesiology residents (3/534 vs. 1/80) or in the incidence of successful blocks (90% for ophthalmology residents vs. 88% for anesthesiology residents). CONCLUSIONS: Regional ocular anesthetic techniques can be safely and successfully taught to residents in anesthesiology.

Public opinion, knowledge, and Medicare reform.

A review of public opinion and focus-group research reveals consistently inadequate understanding of Medicare by the public and misinterpretation of public opinion information by policy advocates. Closer analysis of apparent conflicts in values related to self-sufficiency, personal responsibility, and government, however, reveals strong support for the basic premises of social insurance embodied in Medicare. The likelihood of meaningful policy discussions about Medicare depends, in part, on whether the policy and research communities can find ways to provide the electorate with the knowledge they need to understand the implications of reform.

Thimet oligopeptidase: site-directed mutagenesis disproves previous assumptions about the nature of the catalytic site.

Zinc metallopeptidases that contain the His-Glu-Xaa-Xaa-His (HEXXH) motif generally have a third ligand of the metal ion that may be either a Glu residue (in clan MA) or a His residue (in clan MB) (Rawlings and Barrett (1995) Methods Enzymol. 248, 183-228). Thimet oligopeptidase has not yet been assigned to either clan, and both Glu and His residues have been proposed as the third ligand. We mutated candidate ligand residues in the recombinant enzyme and identified Glu, His and Asp residues that are important for catalytic activity and/or stability of the protein. However, neither of the Glu and His residues close to the HEXXH motif that have previously been suggested to be ligands is required for the binding of zinc. We conclude that thimet oligopeptidase is not a member of clan MA or clan MB and it is likely that the enzyme possesses a catalytic site and protein fold different from those identified in any metallopeptidase to date. The definitive identification of the third zinc ligand may well require the determination of the crystallographic structure of thimet oligopeptidase or one of its homologues.

Cloning and expression of mouse legumain, a lysosomal endopeptidase.

Legumain, a recently discovered mammalian cysteine endopeptidase, was found in all mouse tissues examined, but was particularly abundant in kidney and placenta. The distribution in subcellular fractions of mouse and rat kidney showed a lysosomal localization, and activity was detectable only after the organelles were disrupted. Nevertheless, ratios of legumain activity to that of cathepsin B differed considerably between mouse tissues. cDNA encoding mouse legumain was cloned and sequenced, the deduced amino acid sequence proving to be 83% identical to that of the human protein [Chen, Dando, Rawlings, Brown, Young, Stevens, Hewitt, Watts and Barrett (1997) J. Biol. Chem. 272, 8090-8098]. Recombinant mouse legumain was expressed in human embryonic kidney 293 cells by use of a vector containing a cytomegalovirus promoter. The recombinant enzyme was partially purified and found to be an asparagine-specific endopeptidase closely similar to naturally occurring pig kidney legumain.

Does the choice of anesthetic technique affect the recovery of bowel function after radical prostatectomy?

OBJECTIVES: Return of bowel function after radical prostatectomy surgery may be the limiting factor in discharging these patients from the hospital. Recent studies have shown that postoperative epidural infusion of bupivacaine decreases time to return of bowel function compared with intravenous and epidural morphine in patients after abdominal surgery. This study focuses on the role of the intraoperative anesthetic technique on recovery of bowel function, intraoperative blood loss, and the incidence of postoperative deep venous thrombosis (DVT) in patients undergoing radical retropubic prostatectomy and pelvic lymphadenectomy. METHODS: Forty patients undergoing prostatectomy were randomized to either group A (general endotracheal anesthesia, including muscle relaxation and mechanical ventilation, followed by postoperative intravenous morphine patient-controlled analgesia) or group B (thoracic epidural anesthesia using bupivacaine, combined with "light" general anesthesia using a laryngeal mask airway and spontaneous ventilation, followed by epidural morphine analgesia). Intra- and postoperative data were collected on blood loss, volumes of crystalloid and colloid infused, blood transfused, duration of anesthesia and surgery, anesthetic and surgical complications, time to recovery of bowel function, quality of postoperative pain control, and time to discharge from hospital. Each patient underwent lower extremity venous ultrasonography to detect DVT. RESULTS: Twenty-one patients received general anesthesia and 19 received combined epidural and general anesthesia. Intraoperative blood loss was significantly lower in the epidural group, and times to first flatus and first bowel movement were also shorter in this group. There were no significant differences in duration of anesthesia or surgery, quality of postoperative analgesia, side effects of analgesia, or time to discharge from hospital. There was no DVT detected in any patient. CONCLUSIONS: The combined anesthetic technique of thoracic epidural anesthesia and "light" general anesthesia with spontaneous ventilation decreased intraoperative blood loss and shortened the time to return of bowel function. However, this earlier return of bowel function was not great enough to realize a difference in time to hospital discharge. There was no evidence of increased complications secondary to epidural anesthesia or of prolonged anesthetic time necessary to place epidural catheters.

The relative increase in skin temperature after stellate ganglion block is predictive of a complete sympathectomy of the hand.

BACKGROUND AND OBJECTIVES: Although an increase in skin temperature of the hand implies sympathetic block after stellate ganglion block (SGB), it does not indicate complete sympathetic block unless accompanied by an absence of sweating because skin temperature may increase even with a partial sympathetic block. This study examined the efficacy of the SGB to block sweating in the hand and to determine if the magnitude of temperature change in the hand is predictive of a negative sweat test. METHODS: Fifty-nine SGBs were performed in 30 patients (15 women and 15 men) for diagnostic or therapeutic indications. Stellate ganglion block was performed via an anterior paratracheal approach at C6 using 15 mL 0.25% bupivacaine. Skin temperature was measured bilaterally on the index finger. A cobalt blue sweat test was performed bilaterally pre- and post-SGB on the middle finger. Successful sympathetic block after SGB was considered present when: (a) (change in ipsilateral temperature (postblock-preblock)] (Di)-[change in contralateral temperature] (Dc) > or = 1.5 degrees C; (b) Horner's syndrome present; and (c) sweat test changed from positive to negative. Logistical regression was applied to determine what value of Di - Dc could be used to predict a negative sweat test. RESULTS: Thirty-six percent (21/59) of blocks met all three criteria. Of the blocks where Di - Dc > or = 1.5 degrees C, 72% (21/29) had a negative sweat test post-SGB. Of the blocks where Di - Dc < 1.5 degrees C, 37% (11/30) had a negative sweat test postblock. If Di - Dc > or = 2.0 degrees C, a negative sweat test could be predicted with 69 +/- 12% sensitivity and 85 +/- 10% specificity. CONCLUSIONS: Stellate ganglion block often fails to increase skin temperature in the ipsilateral more than the contralateral hand. A value of Di - Dc > or = 2.0 degrees C was a good predictor of a sympathetic block, but was not sufficient to guarantee a complete sympathetic block of the hand after SGB in all cases. An apparently successful SGB as measured by "usual" clinical criteria may not result in a complete sympathectomy of the hand as is often assumed. Therefore, if obtaining a sympathectomy is important for diagnostic or therapeutic purposes, performing a sweat test provides important confirmatory evidence of the genuine success of the sympathetic block.

The recovery profile of hyperbaric spinal anesthesia with lidocaine, tetracaine, and bupivacaine.

BACKGROUND AND OBJECTIVES: Surgical procedures previously considered too lengthy for the ambulatory surgery setting are now being performed during spinal anesthesia. The complete recovery profile of tetracaine and bupivacaine are now of interest but are not available in the literature. This study was conducted to compare times to ambulation, voiding, and complete block resolution, as well as the incidence of back and radicular pain, after spinal anesthesia with lidocaine, bupivacaine, and tetracaine. METHODS: Twelve adult volunteers underwent spinal anesthesia on three separate occasions with three local anesthetics (lidocaine 100 mg, bupivacaine 15 mg, and tetracaine 15 mg in hyperbaric solutions) in random order and in a double-blind fashion. A 24-gauge Sprotte spinal needle was placed at the L2-3 interspace. The level of analgesia to pinprick was determined moving cephalad in the midclavicular line until a dermatome was reached at which the prick felt as sharp as over an unblocked dermatome. One dermatome caudad to this point was recorded every 5 minutes as the level of analgesia. We also recorded the times to voiding, unassisted ambulation, and complete resolution of sacral anesthesia. RESULTS: There was no difference between tetracaine and bupivacaine in time taken for two- and four-segment regression of the analgesia level. However, times to ambulation and complete resolution of the block were significantly shorter with bupivacaine then with tetracaine. With lidocaine, times to four-segment regression, ambulation, voiding, and complete regression of the block were significantly shorter than with bupivacaine and tetracaine. Time to two-segment regression did not differ among local anesthetics. Back and radicular pain symptoms were reported by three subjects after lidocaine subarachnoid block but not after tetracaine or bupivacaine. CONCLUSION: Among individual subjects, lidocaine exhibited the shortest recovery profile. However, the recovery profiles of the three anesthetics were very variable between subjects. Time to meeting discharge criteria after bupivacaine or tetracaine was faster in a few subjects than that after lidocaine in other subjects. For ambulatory anesthesia, times to two- and four-segment regression do not accurately predict time to readiness for discharge after spinal anesthesia.

Proposals for funding graduate medical education: the Institute of Medicine report in context.

Federal support of graduate medical education (GME) has been accepted as an intrinsic ingredient of the Medicare program since that program's inception. Streams of clinical income generated by teaching hospitals, medical faculty practice plans, Medicaid, and other state and federal sources have also made important contributions to GME. Although it is difficult to ascribe legislative intent precisely, Medicare funding seems to have been based on a 2-fold assumption: that GME was socially beneficial and that there were legitimate costs to teaching hospitals associated with their educational missions, even though such costs were hard to identify specifically. The benefits and costs include the high quality generally ascribed to a teaching hospital environment; extra services and teaching costs; active, unsponsored research; a higher proportion of complex medical conditions and care; and technology development and introduction. The argument for Medicare support of GME is thus partly based on better service to all Medicare beneficiaries, and partly on a broader social investment in education and teaching hospitals, with benefits accruing to both present and future Medicare participants. Teaching hospitals and their young physicians in training are also important in providing care to underserved poor populations.