HIV neuropathogenesis and therapeutic strategies

Abstract Human immunodeficiency virus (HIV)-l neuropathogenesis can be divided into three important components: (i) virus entry into the nervous system; (ii) the role of viral proteins and/or cellular products in neural tissue damage; and (iii) the mechanisms of neuronal injury/death. Both blood derived macrophages or trafficking HIV-1 infected T-lymphocytes have been implicated in viral entry to the central nervous system (CNS). The major cell type harboring productive HIV-1 infection in the nervous system is the perivascular macrophage/ microglia. The HIV-1 infection of brain astrocytes, restricted to the expression of regulatory gene products, may cause astrocyte dysfunction and contribute to neuronal injury or to disruption of the blood-brain barrier (BBB). Studies of cerebrospinal fluid and postmortem tissues reveal chronic inflammation/immune activation in the nervous system during the later stages of HIV-1 infection associated with disruption of BBB integrity. Blood-brain barrier damage may underlie the white matter pallor described in HIV-1 infection and could result in further entry into the CNS of toxic viral or cellular products, or additional HIV-1 infected cells. The HIV infected and activated macrophages/microglia produce excessive amounts of pro-inflammatory cytokines, including tumor necrosis factor alpha, and platelet activating factor. These products are directly toxic to human neurons in vitro. The HIV-1 envelope glycoprotein, gp 120 may stimulate the release of toxic factors from brain macrophages. Blocking N-methyl-D-aspartate (NMDA; or AMPA) glutamate receptors can antagonize candidate toxins of both viral and cellular origin. It has been postulated that (weak) excitotoxicity leads to oxidative stress in neurons and ultimately to apoptosis. Neuronal apoptosis occurs in the brains of both children and adults with HIV-1 infection. This understanding of HIV neuropathogenesis implies that therapeutic strategies should include: (i) anti-retroviral medications to decrease systemic and CNS virus load, and possibly to prevent perinatal transmission of HIV; (ii) anti-inflammatory compounds to decrease the chronic immune activation in microglia and allow the restoration of BBB integrity; and (iii) neuroprotective compounds to reduce neuronal injury and apoptotic death.     

Effect of parenterally administered gold therapy on the course of adult rheumatoid arthritis.

OBJECTIVE: To describe the course of rheumatoid arthritis over 5 years in adults and to evaluate the effect of parenterally administered gold salts on that course. DESIGN: A prospective observational study of adults with rheumatoid arthritis. Data derived from annual interviews with patients from 1983 to 1988 and from physician surveys in 1983 and 1987. SETTING: Rheumatology practices in the community. PATIENTS: The study began in 1982 with 822 adults who had rheumatoid arthritis and were under the care of rheumatologists. INTERVENTIONS: Those selected by rheumatologists in the management of their patients. MEASUREMENTS: Information describing sociodemographic and clinical characteristics, course, and therapy was collected from patients and verified by physician reports. Functional status, measured by the Health Assessment Questionnaire, and the number of painful joints were used as outcome variables. Outcome variables were adjusted for age, sex, disease duration, baseline values of the outcome variable, and the use of four disease-remittive agents other than gold. MAIN RESULTS: Multivariate repeated-measures analysis of variance showed no change in the course of rheumatoid arthritis over 5 years. The use of parenteral gold for at least 2 consecutive years at the start of the observation period produced, on average, no change in the course over 5 years in the two outcome variables. CONCLUSION: In our study of a community-based population of adults with rheumatoid arthritis who were under the care of community rheumatologists, we found that there was, on average, no statistically significant change in function or number of painful joints between 1983 and 1988. Patients receiving parenteral gold therapy for at least 2 consecutive years did not show a statistically significant difference in outcome when compared with those not receiving such therapy.     

The role of general hospitals in the privatization of inpatient treatment for serious mental illness.

For almost three decades, many have regarded general hospital psychiatric units as the most appropriate setting for acute treatment of persons with serious mental illness who were once treated mostly in state hospitals. The extent to which this transfer has taken place and the differences between public and private general hospitals have been unclear. Using data from the 1988 National Mental Health Facilities Study and published data from the 1970s, the authors found that nearly half of all general hospitals providing psychiatric services treat persons with serious mental illness. Significant differences in case and payer mix were observed between public and private general hospitals, although these differences were smaller than in the 1970s. The findings suggest increased involvement by private general hospitals in treating patients reimbursed by public payers, but the findings also indicate that persons with serious mental illness and those using Medicaid are still more prevalent in public general hospitals than in private ones.     

Evaluation of radical prostatectomy capsular margins of resection. The significance of margins designated as negative, closely approaching, and positive

Capsular margins of resection in radical prostatectomy specimens performed for carcinoma of the prostate are difficult to assess because of the scant soft tissue removed with the prostate. There is little objective information as to the validity of what are designated as positive or negative capsular margins of resection. From January 1, 1984 through June 30, 1989 there were 40 radical prostatectomies performed in which the prostate was initially removed leaving the neurovascular bundle within the patient in order to preserve potency. However, based on the surgeons' gross examination of the prostate at the time of radical prostatectomy, the neurovascular bundle was then subsequently removed during the same operation and submitted to pathology as a separate specimen. In these 40 cases the capsular margin in the region of the neurovascular bundle was assessed blindly without knowledge of tumor presence or absence in the subsequently resected neurovascular bundle, and then compared to whether the neurovascular bundle contained tumor. Of the 10 cases called positive based on review of the radical prostatectomy, only six neurovascular bundles (60%) contained tumor. Eight cases had equivocal margins with tumor extending just to the inked margin, and only one (12.5%) had tumor in the neurovascular bundle. All 20 cases with negative assigned margins had complete removal of tumor from this area with none of the neurovascular bundles containing tumor. This study demonstrated that negative capsular margins in radical prostatectomy specimens often contain only a scant amount of soft tissue. Of the 33 cases with true negative margins, the amount of soft tissue between the inked margin and tumor was only greater than 1 mm in two cases and less than or equal to 1 m in 20 cases (less than 0.5 mm in 13 cases with less than 0.25 mm in eight of these cases). Furthermore, 11 cases with tumor extending to the inked margin of resection showed no residual tumor in additional tissue removed from these regions.     

The effect of high-dose salmon calcitonin on bone mineral metabolism in the normal rat

Summary The paucity of information on the effect of long-term high-dose salmon calcitonin administration on normal bone mineral metabolism and histology prompted an investigation of the influence of high-dose synthetic calcitonin in the rat. Serum ionized calcium, osteocalcin or BGP (bone gla protein), and immunoreactive PTH were measured serially during calcitonin administration and bone histomorphometry analyzed at 6 weeks (after sacrifice). Daily injections of salmon calcitonin, 0.4 IU/100 g (group B) and 2 IU/100 g (group C), resulted in significant hypocalcemia at 4 hours for both experimental groups (P<0.004). Serium iPTH was significantly higher over the study period for both groups administered calcitonin. Serum BGP levels were significantly lower than controls during the study in group C (P<0.002) and to a lesser extent in group B (P<0.05). In group C, bone histomorphometry revealed increased resorption (onteoclast count), decreased trabecular bone volume, and decreased double-labeled tetracycline surface (bone formation). In group B an increase in osteoclast count but no alteration in bone formation was observed. To assess the role of PTH in the above findings, high-dose calcitonin was administered to parathyroidectomized rats. All of the above changes in bone histomorphometry were not observed in this group of animals. In conclusion, high doses of calcitonin promote hypocalcemia, secondary hyperparathyroidism, and osteoclastosis in the normal rat in a dose-dependent manner with very high-dose calcitonin impairing bone formation.     

12-month outcome of patients with major depression and comorbid psychiatric or medical illness (compound depression)

OBJECTIVE: Inpatients with major depressive illness often have coexistent nonaffective psychiatric and/or medical conditions. The authors' objective is to address the following questions: 1) What is the effect of comorbid illness on the severity of major depression and associated psychosocial factors? 2) How does the course of depression differ for patients with and without concurrent illness? 3) Do patients with compound depression differ in rate of recovery and time to recovery from patients with pure depression? METHOD: The subjects were 78 patients with a DSM-III diagnosis of major depression who were consecutively admitted to an acute care university-affiliated psychiatric hospital; 37 of these patients had major depression only and 41 had major depression compounded by a coexisting axis I, II, or III condition. The patients were studied while hospitalized and for 12 months after hospital discharge. Instruments used included the Modified Hamilton Rating Scale for Depression, the Global Assessment Scale, and the Social Readjustment Rating Scale. RESULTS: Patients with compound depression reported significantly poorer functioning over the 12-month follow-up period and had lower recovery rates than the patients with pure depression. There were no differences in recovery rates between men and women with compound depression, but significantly more men than women with pure depression recovered. CONCLUSIONS: Compound depression is a common clinical occurrence, the course of illness is more difficult for patients with compound depression than for patients with pure depression, and the recovery rate of patients with compound depression is lower than that of patients with pure depression.     

Changes in heart rate and rhythm after intramuscular succinylcholine with or without atropine in anesthetized children

The effects of intramuscular injections of succinylcholine with or without atropine on heart rate and rhythm were studied in 50 unpremedicated children 6-18 months of age. All had anesthesia induced with N2O-O2 and halothane 2% by face mask. Sixty seconds later, one of four study drugs or drug combinations was injected into the deltoid muscle of patients in groups 1-4. Following injection, halothane concentration was reduced to 1%, and ventilation was controlled. Patients given atropine only (0.02 mg/kg), succinylcholine only (4 mg/kg), or a combination of both (4 mg/kg succinylcholine plus 0.02 mg/kg atropine) showed transient increases in heart rate to 106 +/- 7.5%, 113 +/- 11.8%, and 109 +/- 10.1% (mean +/- SD) of control, followed by a decrease to 78 +/- 6.7%, 79 +/- 9.4%, and 80 +/- 10.5%, respectively, in 2-3 min after injection. Patients given a combination of succinylcholine (4 mg/kg) plus a higher dose of atropine (0.03 mg/kg) also had a transient increase in heart rate to 107 +/- 7.5%, followed by a decrease to 82 +/- 11.8% 2 min after injection. However, this group differed from the other three groups in presenting a second, prolonged increase in heart rate to 115 +/- 9.0% of preinjection levels. Patients in group 5 (controls) received no injections. Their heart rate decreased to 76 +/- 10.78% of preinduction level within 90 sec of induction, and remained unchanged thereafter. We conclude that succinylcholine (4 mg/kg) can be used intramuscularly with or without atropine (0.02 mg/kg) in lightly anesthetized young children without producing severe bradycardia.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of the subfornical organ in the drinking behavior of the pigeon

Pigeons with radiofrequency lesions that damaged the subfornical organ (SFO) (n = 4) or that isolated it from adjacent structures (n = 5), but not sham-lesioned pigeons, were unresponsive to blood-borne (i.p.) ANG II (100 micrograms/pigeon) in the immediate postoperative period and for 60 days thereafter. These animals were less sensitive to hypovolemic challenge (20% PEG), but they responded normally to 24 h of water deprivation and to cellular dehydration. Despite their unresponsiveness to bloodborne ANG II, the lesioned pigeons drank normally to 10 ng of i.c.v. ANG II given as early as 10 days after surgery, and they drank reliably and vigorously but less in total volume to 100 ng i.c.v. They also drank quickly, vigorously, and in normal total volume to i.c.v. tachykinins and bombesins, and to the peripheral (i.p.) bombesins. Peripheral (i.m.) tachykinins produced only low volume and variable drinking in all birds tested regardless of brain damage. The SFO of the pigeon, like that of the mammal, is essential for drinking evoked by blood-borne ANG II and is not necessary for thirst aroused by ANG II acting from within the cerebral ventricles. Lastly, it does not mediate the dipsogenic effects of the tachykinins or the bombesins.     

Regionalization of ST-segment elevation acute coronary syndromes care: putting a national policy in proper perspective.

A uniform policy for regionalization of ST-segment elevation myocardial infarction (STEMI) care raises several concerns. Transferring all STEMI patients to obtain primary percutaneous coronary intervention (PCI) may be less effective than transferring only high-risk STEMI patients. Delays in time to treatment >60 min associated with transferring patients for primary PCI may result in increased mortality for the average patient as compared with providing immediate fibrinolytic therapy at their initial hospital; yet more than 95% of patients transferred for primary PCI in the U.S. exceed this 60-min benchmark. Superior outcomes associated with treatment at higher-volume regional STEMI centers are inconsistent among centers, and there is no direct evidence that patients will benefit by a transfer to a high-volume hospital from a low-volume hospital. Published data suggest as many as 800 PCI patients would need to be transferred to a high-volume PCI hospital to avoid a single death at a low-volume PCI hospital. Although European randomized trial data suggest transferring patients with STEMI for primary PCI may be superior to immediate fibrinolytic therapy, these findings are unlikely to generalize to the U.S. health care system given size, geography, and organization. ST segment elevation myocardial infarction care regionalization would require a massive redistribution of health care resources, depriving several hospitals of advanced cardiac care facilities, expertise, and associated revenue. Clearer evidence of the benefits and discussion of potential harms are needed before adopting a national STEMI regionalization policy.