Bridges between nervous and immune systems: their disconnection and clinical consequences.

Nervous and immune systems are connected by several mutual links, thus constituting a diffuse functional network in the body. In particular, neurohormones, neuropeptides, and cytokines represent the major mediators of the so-called psychoneuroendocrinoimmune axis. In this review, special emphasis is placed on certain pathologies characterized by a disconnection of the existing bridges between nervous and immune systems. For instance, spinal cord injury (SCI) is a clinical condition in which loss of neurons and very poor axon growth represent the main features. The role played by infiltrating and resident immunocompetent cells is still debated in SCI. However, to enhance axon growth in SCI, current therapeutic attempts are based on the stimulation of the immune response within the central nervous system, thus triggering either cell-mediated or humoral immune responsiveness.

Use of noninvasive electroacupuncture for the treatment of HIV-related peripheral neuropathy: a pilot study.

OBJECTIVES: The main objective of this study was to test the hypothesis that low-voltage non-invasive electroacupuncture will improve the condition of neuropathic human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients. DESIGN: A prospective study using HIV/AIDS patients who had antiretroviral drug-induced neuropathy. Eleven patients were enrolled, but complete data was obtained from only 7. Non-invasive skin electrodes were placed on leg acupuncture points BL60, ST36, K1, LIV3, and low-voltage current passed for 20 minutes every day for 30 days. Patients were assessed preintervention and postintervention with MOS-HIV 30-item instrument questionnaire and tibial H-reflex was similarly recorded from the right calf muscle. RESULTS: There was improvement in the condition of all 7 patients. They felt much better and reported feelings of increased physical strength. Outcomes on MOS-HIV 30-item instrument showed significant overall improvement in functional activities (pre 33+/-10, post 38.4+/-9.6, p = 0.02 MANOVA). This was confirmed by postintervention H-reflex parameters; H-max and direct muscle response (M-response) amplitudes were potentiated in relation to pretreatment values (H-max: pre = 1.19+/-1.2, post = 2.68+/-1.9, p<0.05; M-response: pre = 0.93+/-1.1, post = 2.34+/-1.8, p<0.05); M-response latency decreased in relation to pretreatment value (pre = 9.7+/-1.8, post = 7.8+/-1.9, p<0.01). CONCLUSION: The results support the hypothesis that low-voltage electroacupuncture will improve the condition of the neuropathic HIV/AIDS patient.

Physical therapy management for the patient with HIV. Lower extremity challenges.

Disability assessment and rehabilitation intervention have implications for specific stages of HIV disease, with the intention of maximizing overall function and decreasing the burden of care. The AIDS epidemic has challenged communities to develop and to mobilize care networks for persons infected with HIV. A major part of that mobilization has been a push toward community and home-based services. Reliable and valid functional assessment data are necessary to evaluate HIV-related disability changes over time for patients in the hospital and at home. Epidemiologic data also hold implications for rehabilitation healthcare workers in terms of expertise in HIV-specific areas and on the staffing level. Access to rehabilitation services will need to be considered by public policymakers and financial concerns will need to be explored. Because individuals with HIV and AIDS are living longer and with greater levels of health, the chronicity of the disease warrants community support and long-term care. Various functional and quality-of-life measures can assist in the development of resources and medical interventions. As survival increases, rehabilitation professionals can anticipate more referrals for the assessment and management of physical disability in persons with HIV infection. A critical task for health service research is to ensure that HIV healthcare settings deliver optimum services at reasonable costs. Optimal care requires maximizing autonomous functioning and reducing periods of disability and dependence.

Physical therapy management of HIV disease: a retrospective study.

AIDS: A study identified the types of conditions referred for outpatient physical therapy services at Thomas Street Clinic in Houston, Texas, as well as the therapy interventions used and outcomes of treatment. Researchers reviewed 74 patient records between January and June 1992. Eighty percent of the referrals for physical therapy were for pain management, and of these, 43 percent were for musculoskeletal problems, 27 percent were for peripheral neuropathy problems, and 15 percent were for general rehabilitation. Results indicate that physical therapy can play a vital role in reducing the need for hospitalization, for pain management of peripheral neuropathies, and for musculoskeletal complaints of people with HIV disease.^ieng

D-amino acid scan of endothelin: importance of amino acids adjacent to cysteinyl residues in isomeric selectivity.

A systematic approach to map the functionally important determinants of endothelin-1 (ET-1) by a D-amino acid scan is described. Correct orientation of the amino acid side chains was generally of paramount importance both for binding at the ETA receptor and for contracting activity. This was particularly valid for positions 2, 8, 14, 16-21 (the four Cys residues were kept unaltered). Nevertheless, increment of binding affinity was observed by inversion of configuration at positions 6, 7, 9 and 10. In addition, [D-Lys9]ET was an agonist about four times more potent than the natural compound. Usually both 1,4- and 1,3-isomers (corresponding, respectively, to the correct and misfolded disulfide bridges of ET) were obtained, and usually the isomer formed in larger amount had the higher HPLC retention time and the higher biological activity. However, four out of seventeen single-point D-amino acid analogues could be isolated only in one isomeric form. In three cases (D-Ser2, D-Ser4, D-Val12), the inverted amino acid was adjacent to a Cys residue, and in one case (D-Lys9) it was one amino acid apart, thus suggesting a possible effect of the bridged cysteinyl residues in isomeric selectivity.

Side-reactions in peptide synthesis. 2. Formation of by-products in the large-scale synthesis of THF-gamma 2 by solution synthesis.

The impurities which formed in the large-scale synthesis of THF-gamma 2, an immunomodulatory peptide of formula H-Leu-Glu-Asp-Gly-Pro-Lys-Phe-Leu-OH, were identified by a combination of analytical methods, and their structure confirmed by synthesis. Most impurities originated from side-reactions involving the aspartyl residue (cyclization, beta-aspartyl formation and cleavage). Based on this knowledge, modifications were introduced into the work up and the purification procedure which resulted in a very pure final product (> 99% by RP-HPLC).

Alanine scan of endothelin: importance of aromatic residues.

A systematic approach to map the functional important determinants of endothelin-1 (ET) by an alanine scan is described. Studies on the in vitro receptor binding affinity and on the agonist contracting activity defined that residues Asp8, Tyr13, Phe14, Leu17, and Trp21 were of major biological significance. A striking observation was that four out of these five sites were hydrophobic amino acids. Ala analogues of the aromatic residues at position 13, 14, and 21 displayed sharply reduced receptor binding affinity (< 2% of ET) and can be considered important for receptor contact. Ala analogues of Asp8 and Leu17 lost most (> 90%) of the agonist activity but retained a receptor affinity nearly equivalent to ET and can be considered to be important for signal transduction. Three other positions, Val12, Asp18, and Ile20 (which are adjacent to the biologically important sites of Tyr13, Leu17, and Trp21), resulted as partially tolerant to Ala substitution, retaining 14-50% of the potency of ET. Ala analogues of the Et isomeric disulfide arrangement (Cys1,11 and Cys3,15) were always less active than the corresponding analogues with the native disulfide pairings (Cys1,15 and Cys3,11).

Bombesin receptor antagonists. 5 new irreversible alkylating analogues.

New alkylating bombesin analogues were synthesized in order to increase their solubility and stability in aqueous solutions. The best compromise between these parameters and the biological properties (receptor binding and antagonistic activity) was achieved with 4-[bis(2-chloro-ethylamino)]benzoyl derivatives of the BN (7-14) octapeptide carrying a (13-14) reduced peptide bond independently of the presence of a His12 residue, either free or protected.

Chemically unambiguous peptide immunogen: preparation, orientation and antigenicity of purified peptide conjugated to the multiple antigen peptide system.

We described a novel and simple approach to prepare chemically unambiguous peptide immunogen using the multiple antigen peptide (MAP) approach. This approach requires the conjugation of two purified components: a chloroacetylated oligomeric lysine core matrix and a synthetic peptide containing cysteine at either the carboxyl or amino terminus. The resulting MAP is structurally unambiguous and contains a quantifiable amount of peptide antigens. Furthermore, this method also provides a flexible strategy to link a peptide antigen to the core matrix at the desirable orientation to mimic the native molecule. The carboxyl fragment 43-50 of human transforming growth factor alpha (TGF alpha) was used as a test model for this approach. Antipeptide antibodies did not recognize the "reverse immunogen" in which the peptide was attached to the MAP core matrix at a reverse orientation. To determine the specificity of the antibodies, we used two series of point-substituted TGF alpha analogs containing either alanine or the corresponding D-amino acid replacement to map the antigenic site. The alanine analogs were used to determine the contribution of the side chain while the D-amino acid analogs were used to determine the importance of backbone conformation. The antigen site was found to consist of four residues (Asp47-Leu48-Leu49-Ala50) at the distal end of the peptide-MAP conjugate. The results provide a clear explanation for the specificity of the antipeptide antibodies and their failure to recognize the "reverse immunogen" since the distal and the flexible end of the peptide-MAP construct constitutes the antigenic site. Furthermore, our results also suggests a strategy of placing the antigenic portion of a short-peptide at the distal end in the MAP approach to prepare immunogen.

Bombesin receptor antagonists. 3. Irreversible alkylating analogues: melphalan derivatives.

Bombesin (BN)-like peptides (such as GRP, gastrin-releasing peptide) are autocrine growth factors for small cell lung carcinoma (SCLC). BN receptor antagonists can therefore find clinical application in the treatment of this highly malignant disease. The present paper deals with a new class of bombesin analogues carrying a nitrogen mustard at their N-terminus. Due to the irreversible binding to the BN receptor(s), these peptides eventually block the mitogenic effects of the natural ligand(s), regardless of their intrinsic "agonistic" or "antagonistic" structures. In Swiss 3T3 fibroblasts they inhibit [125I]GRP binding in the nanomolar/micromolar range. According to their "agonistic" or "antagonistic" structural features, they do or do not induce [3H]thymidine incorporation and p 115 phosphorylation. In competition experiments, alkylating "antagonists" selectively inhibit BN-induced thymidine incorporation either when given simultaneously with or 24 hours before the BN challenge. Alkylating "agonists" display antagonistic effects only in the sequential treatment.

Mutagenic contaminants in synthetic peptides obtained by an azide coupling.

Hormone-like peptides are, almost by definition, not mutagenic. It was, therefore, unusual to find that some batches of peptides synthesized by azide coupling were mutagenic in the Ames test. One of these peptides, eledoisin, showed mutagenic activity particularly in Salmonella typhimurium TA 1535 without metabolic activation. This activity was independent of the peptide purity determined by HPLC and a dose response relationship was observed at concentrations over the solubility limit of the peptide in the assay medium. We therefore suggested that the mutagenic effect might be due to the presence of chemically undetectable, water-soluble impurities, which could be removed by counter-current distribution. If, however, the same final coupling was carried out by the mixed anhydride procedure, no mutagenic activity was observed. Consequently, we considered that the mutagenicity detected was due to traces of hydrazoic acid salts arising during azide formation in the coupling step. In fact only the product of the coupling reaction between the pivotal intermediates was mutagenic.

Pain Management and Neuromuscular Reeducation for the HIV Patient.

As a multisystem chronic illness, two areas come to the forefront for management by the rehabilitation specialist. Pain and neuromuscular deficits may be a result of direct insult by the human immunodeficiency virus (HIV) or opportunistic infections affecting functional abilities. A brief overview of pathologic findings reveals that the types of pain experiences is based upon the disease processes that are occurring secondary to HIV. The management of pain and resultant functional changes depends on the source, symptoms and signs of pain. Physical and Occupational therapists are key health care professionals to conduct pain assessments and evaluate functional impairment to better employ non-invasive techniques for management of HIV complications. This article presents various modalities and modes of therapeutic intervention to enhance full participation of the person with HIV in activities of daily living.

Progressive resistance exercise: effect on muscle function and anthropometry of a select AIDS population.

Substantial body tissue wasting has been reported in acquired immune deficiency syndrome (AIDS) patients. The purpose of this investigation was to determine if progressive resistance exercise (PRE) would improve muscle function and increase body dimensions and mass in AIDS patients. The subjects were 24 male outpatient volunteers, status posttherapy for acute pneumocystis carinii pneumonia. Subjects were randomly assigned to control (n = 12) or experimental (n = 12) subsets. All subjects underwent muscle function testing on 12 variables of torque, force, power, and work; three variables of anthropometry were assessed. The experimental group engaged in PRE three times per week for six weeks. The control group did not exercise beyond their usual daily living activities. Both groups were retested at the end of six weeks. In comparison to the control group, the experimental group significantly increased in 13 of the 15 study variables. Thus, during the nonacute stage of AIDS, physiologic adaptation occurred that improved muscle function and increased body dimensions and mass.