Unconscious mental functioning.
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Anxiety↗
Biomedical subjects
J Weiss
Publications and source records attributed to J Weiss.
Behaviour and physiology of castrated rats with different episodic schedules of testosterone restoration.
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Animals↗
Human T-cell lymphotropic virus-type I.
HTLV-I is a retrovirus now identified as the etiologic agent of two diverse disease processes: ATLL, an aggressive T-cell malignancy; and TSP/HAM, a chronic progressive myelopathy. Transmission can occur horizontally through blood transfusions, IV drug abuse and sexual intercourse. Vertical transmission may also occur. Available diagnostic modalities are serologic in nature and include the EIA and the more specific confirmatory assays WIB and RIPA. These studies are thus far suboptimal in terms of sensitivity and specificity, and await refinement. DNA amplification by the polymerase chain reaction seems to hold the most immediate diagnostic promise for the future. AZT apparently is not useful clinically, and current treatment is only palliative in nature. The diverse diseases caused by HTLV-I underscore the insidious nature of the Retroviridae family. These subtle cell-associated pathogens will undoubtedly be shown to play a significant role in other disease processes of uncertain etiology.
HTLV-I Infections↗
Separation of sublethal and lethal effects of the bactericidal/permeability increasing protein on Escherichia coli.
Binding of the bactericidal/permeability increasing protein (BPI) of granulocytes to Escherichia coli promptly produces several discrete outer envelope alterations and growth arrest without major impairment of bacterial structure or biosynthetic capabilities, raising the question whether these early effects of BPI are sufficient to cause bacterial death. In this study, the bactericidal action of BPI was examined more closely. We have found that bovine or human serum albumin blocks bacterial killing without preventing BPI binding or an increase in outer membrane permeability. Moreover, addition of serum albumin after BPI results in growth resumption without displacement of bound BPI and without (early) repair of the envelope alterations. These effects are opposite to those produced by Mg2+ (80 mM), which displaces greater than 85% of bound BPI and rapidly initiates outer envelope repair without restoration of bacterial growth. The extent of rescue by serum albumin depends on the time and pH of preincubation of BPI with E. coli: e.g., for E. coli J5 treated with human BPI, t1/2 = 79 min at pH 7.4 and 10 min at pH 6.0. The serum albumin effects on BPI action are the same in wild-type E. coli and in a mutant strain lacking an activatable phospholipase, indicating that serum albumin does not act by sequestering membrane-damaging products of bacterial phospholipid hydrolysis. The progression from reversible to irreversible growth arrest, revealed by the subsequent addition of serum albumin at different times, is paralleled by a decrease in amino acid uptake and an increase in the permeability of the cytoplasmic membrane to o-nitrophenyl-beta-D-galactoside. These findings demonstrate at least two stages in the action of BPI: (a) an early, reversible, sublethal stage in which BPI has effects on the outer envelope and causes growth arrest, and (b) time- and pH-dependent progression to a lethal stage, apparently involving cytoplasmic membrane damage, possibly caused by penetration of a small subpopulation of BPI.
Animals↗
Bacterial phospholipid hydrolysis enhances the destruction of Escherichia coli ingested by rabbit neutrophils. Role of cellular and extracellular phospholipases.
Escherichia coli ingested by PMN are promptly growth arrested but undergo limited destruction. We have studied bacterial phospholipid hydrolysis as a possible limiting factor in the disassembly of ingested E. coli, comparing the fates, during phagocytosis by rabbit peritoneal exudate PMN, of three isogenic strains, differing in their content of the pldA gene encoding the principal E. coli phospholipase A (PLA), i.e., pldA-, pldA+, pldA (the latter strain bearing the pldA gene in a multicopy plasmid resulting in a 20-fold increase in PLA content). Ingestion and growth inhibition (greater than 99% within 15 min) were the same for the three strains, but phospholipid degradation differed according to bacterial PLA content: pldA up to 60%, pldA+ up to 30%, and pldA- up to 20%. Since the pldA- strain has no activatable PLA, phospholipid degradation in this strain demonstrates the action of a PMN PLA. Added PLA2-rich ascitic fluid (AF) or purified AF PLA2 increased the rate and extent of degradation of the pldA- strain, provided the enzyme was added before ingestion was complete. 125I-AF-PLA2 binds to both E. coli and PMN and thus can enter the vacuole during phagocytosis. Although up to 50-fold more AF-PLA2 than the PLA2 content of the PMN could be loaded into the PMN in this way, degradation of pldA- E. coli did not exceed 30%. Increased phospholipid degradation had no effect on the degradation of bacterial macromolecules. In contrast, bacterial disassembly manifest as structural disorganization, release of bacterial protein derived material, and inhibition of protein synthesis were markedly enhanced when greater than 50% of prelabelled bacterial phospholipids were degraded. These findings reveal a link between envelope phospholipid degradation and overall bacterial destruction, suggesting therefore that factors limiting PLA action limit the destruction of E. coli ingested by PMN.
Animals↗
Separation of sublethal and lethal effects of polymorphonuclear leukocytes on Escherichia coli.
Escherichia coli ingested by PMN promptly stop growing and form no colonies in nutrient agar, but metabolize near normally for up to several hours. The bactericidal/permeability increasing protein (BPI) of PMN also inhibits E. coli growth without initial metabolic impairment. We recently showed that BPI-treated E. coli, although unable to grow in normal nutrient agar, can form colonies in this medium plus 0.1% BSA, as long as their metabolism is maintained, indicating that biochemical impairment is a better indicator of death than growth arrest (1990. J. Clin. Invest. 85:853-860). We have now reexamined the fate of ingested E. coli. Rabbit PMN ingest greater than 85% of several rough E. coli strains in 15 min, but greater than 80% of these bacteria, while unable to form colonies in conventional agar, grow normally on agar plus 0.1% BSA. Thus, the PMN under these conditions promptly stop growth of ingested E. coli without killing. Adding nonlethal concentrations of normal human serum (NHS) before, but not after ingestion, accelerates killing and, in parallel, loss of bacterial metabolism (t1/2 less than 0.5 h vs. greater than 3 h, respectively, with and without NHS). The rapid killing of both rough and smooth E. coli pretreated with NHS is lost after C7 depletion (C7-D) and restored when C7 is replenished. Similar results are obtained with human PMN. In contrast, ingested Staphylococcus epidermidis, opsonized with either NHS or C7-D serum rapidly stop metabolizing and do not form colonies in nutrient agar with or without BSA. Respiratory burst activity is the same during ingestion of E. coli (with or without NHS) and S. epidermidis. Killing of E. coli J5 (however, not of O111-B4) by BPI is also accelerated by pretreatment with NHS but not C7-D human serum. These findings indicate that late complement components are needed for efficient killing of both rough and smooth E. coli by PMN, and that BPI is the principal intracellular agent acting on ingested rough E. coli.
Animals↗
Gonadotropin-releasing hormone-induced stimulation and desensitization of free alpha-subunit secretion mirrors luteinizing hormone and follicle-stimulating hormone in perifused rat pituitary cells.
A pulsatile pattern of hypothalamic GnRH stimulation is necessary for the maintenance of pituitary LH and FSH secretion, with continuous GnRH leading to a decrement in response. Although the physiological pattern of free alpha-subunit secretion closely mimics that of LH, several reports have indicated that free alpha-subunit is not desensitized by continuous GnRH stimulation. To explore the basis of this phenomenon, we have evaluated the responses of all three gonadotrope secretory products to carefully coordinated administration of pulsatile and continuous GnRH in a dispersed rat pituitary perifusion system. Sensitivities (ED50) to GnRH fell within a narrow range for free alpha-subunit (11.5 nM), LH (12.9 nM), and FSH (17.3 nM), although a greater mass of LH than free alpha-subunit or FSH was released after each pulse of GnRH. The response to a standard GnRH pulse (10 nM) administered every 15, 30, or 120 min for 9 h was very stable, with no evidence of priming, summation, or loss of response. LH, FSH, and free alpha-subunit did, however, show significantly (P less than 0.05) higher pulse amplitude with longer interpulse intervals. In contrast to previous observations in vivo, the three gonadotrope secretory products showed parallel desensitization in response to continuous infusions of GnRH. This loss of response was significant (P less than 0.05) after exposure to as little as 0.1 (FSH) to 0.5 nM (LH and alpha-subunit) GnRH for 2 h or to higher concentrations of GnRH (10 nM) for as little as 15 min (LH, FSH, and alpha-subunit). These concentrations and durations of GnRH stimulation are within the range of values measured in vivo. We conclude that 1) free alpha-subunit, LH, and FSH have similar concentration and frequency responses to pulsatile GnRH, although the absolute amount of hormone released is different for each secretory product; 2) the frequency of pulsatile GnRH stimulation can function as an independent determinant of secretion for each of the three products; and 3) in contrast to observations in vivo, free alpha-subunit, LH, and FSH secretion desensitize similarly after exposure to concentrations or durations of GnRH that may occur in vivo. These observations raise the possibility that desensitization plays a role in the physiological regulation of gonadotrope secretion.
Animals↗
Divergent responses of gonadotropin subunit messenger RNAs to continuous versus pulsatile gonadotropin-releasing hormone in vitro.
Episodic GnRH input is necessary for the maintenance of LH and FSH secretion. In the current study we have assessed the requirement of a pulsatile GnRH signal for the regulation of gonadotropin alpha- and beta-subunit gene expression. Using a dispersed rat pituitary perifusion system, GnRH (10 nM) was administered as a continuous infusion vs. hourly pulses. Secretion of free alpha-subunit, LH, and FSH were monitored over 5-min intervals for the entire 12-h treatment period before the responses of alpha, LH beta, and FSH beta mRNAs were assessed. Basal release of all three glycoproteins declined slowly over 6-8 h before reaching a plateau. The cells were responsive to each pulse of GnRH, but continuous GnRH elicited only a brief episode of free alpha-subunit, LH, and FSH release, followed by a return to unstimulated levels. Despite the similar patterns of secretion, differences were observed in the responses of gonadotropin mRNAs to the two modes of GnRH. alpha mRNA increased in response to continuous (1.6-fold) or pulsatile (1.7-fold) GnRH. FSH beta mRNA was suppressed to 48% of the control value after continuous GnRH, but was stimulated over 4-fold by the pulses. LH beta mRNA was unresponsive to either treatment paradigm. We conclude that in vitro 1) alpha mRNA levels are increased in response to GnRH independent of the mode of stimulation; 2) under the conditions studied, LH beta mRNA levels are unresponsive to either mode of GnRH input; and 3) the response of FSH beta mRNA to GnRH is highly dependent on the mode of administration, with levels depressed in response to continuous GnRH, but stimulated by pulsatile GnRH.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Serious infectious complications of midsternotomy: a review of bacteriology and antimicrobial therapy.
49 patients with severe infectious complications of midsternotomy incision were treated at our referral center over a 3-year period. 43 species of microorganisms were identified in 38 patients, the most common being Pseudomonas aeruginosa (37%) and Staphylococcus aureus (30%). Most of the patients underwent aggressive debridement and chest wall reconstruction by muscle transposition in combination with antimicrobial therapy. Antimicrobial therapy was given perioperatively according to the in vitro susceptibility of the organisms. Treatment was continued beyond this period for 2-3 weeks in patients with extensive deep seated infection or in those with positive cultures from intraoperative specimens. Some patients needed a longer course of up to 6-8 weeks antimicrobial therapy because of insufficient response to the shorter course. In all, 45/49 patients had complete wound healing. 28 recovered within 2-5 weeks and 16 required a more protracted course with additional surgery in 8; 1 wound did not heal after 20 months and 4 patients died from non-infectious complications. Due to the lack of specific guidelines in the literature as to the proper choice and length of administration of antimicrobial therapy for midsternotomy wound infection, and in view of these favorable results, we recommend our protocol in the treatment of midsternotomy wound infection (in combination with appropriate surgery).
Anti-Bacterial Agents↗
High capital costs could trigger losses. Interview by Richard L. Clarke.
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Accounts Payable and Receivable↗
[Solarium pseudoporphyria. Report of a case and review of the literature].
Excessive UVA radiation can cause a porphyria-like bullous condition in fair-skinned persons. Another patient with a solarium-pseudoporphyria is presented, and a review of the cases published so far is given.
Adult↗
Regulation and role of phospholipases in host-bacteria interaction.
Deacylating phospholipases play essential roles in numerous biological events, requiring tight control of hydrolytic activity. Most cells, unless stimulated or perturbed, exhibit little phospholipid turnover. Activation of phospholipases A (PLA) is usually triggered by membrane perturbing conditions or agents. Some activators indiscriminately activate any PLA, others are highly specific. Our studies concern an activator that is a potent bactericidal protein with membrane-perturbing properties, isolated from polymorphonuclear leukocytes (PMN), that is only cytotoxic for gram-negative bacteria and primarily responsible for the fate of several gram-negative bacterial species, ingested and killed by the PMN. It is this protein that activates the hydrolysis of the phospholipids of the killed bacteria (E. coli) by three PLA: 1) an E. coli PLA, the pldA gene product; 2) a PLA2 of PMN; 3) a soluble PLA2 in the extracellular fluid of an inflammatory exudate. However, this activator protein does not trigger the action of many other PLA2, all members of a highly conserved class of PLA. Our structural studies (including genetic engineering) of both responsive and non-responsive PLA2 have revealed that the amino acid composition and sequence of the NH2-terminal alpha-helix of the PLA2 molecule are major determinants of the ability of the PMN protein to activate a given PLA2. Our results provide another demonstration that these important enzymes have diverged during evolution to perform different biological functions.
Animals↗
[Risk factors for the development of malignant melanoma in West Germany. Results of a multicenter-case control study].
In this multicenter case-control study (1,079 melanoma patients, 778 control persons), the significance of the well-known risk factors for the development of malignant melanoma (MM) was assessed for a German population. The multifactorial analysis of the data confirmed the total number of melanocytic nevi (MCN) as the most robust indicator for an increased melanoma risk. For persons with more than 50 MCN the relative risk was 4.8 times as high as for persons with fewer than 10 MCN. Hair color was found to be another valuable indicator. In persons with red hair the risk of MM was 4.7 that in individuals with black hair. Remarkably fair persons with skin type 1 (always sunburn, never tanning) had two times the risk of that in persons with skin type 4 (never sunburn, always tanning). The habit sun bathing for recreation showed no influence on the development of melanoma. A 2.7 x increased melanoma-risk was detected in persons with occupational sun exposure and out of doors work.
Case-Control Studies↗
Cloning of the cDNA of a human neutrophil bactericidal protein. Structural and functional correlations.
The bactericidal permeability increasing protein (BPI) is a 50-60-kDa membrane-associated protein isolated from granules of polymorphonuclear leukocytes. A full-length cDNA clone encoding human BPI has been isolated and the derived amino acid sequence reveals a structure that is consistent with previously determined biological properties. BPI may be organized into two domains: the amino-terminal half, previously shown to contain all known antimicrobial activity, contains a large fraction of basic and hydrophilic residues. In contrast, the carboxyl-terminal half contains more acidic than basic residues and includes several potential transmembrane regions which may anchor the holoprotein in the granule membrane. The cytotoxic action of BPI is limited to many species of Gram-negative bacteria; this specificity may be explained by a strong affinity of the very basic aminoterminal half for the negatively charged lipopolysaccharides that are unique to the Gram-negative bacterial envelope. The amino-terminal end of BPI exhibits significant similarity with the sequence of a rabbit lipopolysaccharide-binding protein, suggesting that both molecules share a similar structure for binding lipopolysaccharides.
Amino Acid Sequence↗
Preferential binding of the neutrophil cytoplasmic granule-derived bactericidal/permeability increasing protein to target bacteria. Implications and use as a means of purification.
The specificity of the basic bactericidal/permeability increasing protein (BPI) of polymorphonuclear leukocytes (PMN) for gram-negative bacteria is attributable to its strong attraction for the negatively charged envelope LPS. The antibacterial activity of PMN homogenates or extracts toward Escherichia coli corresponds to their BPI content and is blocked by anti-BPI IgG, suggesting that BPI action is unaffected by the presence of other PMN proteins. To test if BPI is preferentially bound to E. coli when other antibacterial proteins are present, we have measured binding in buffered (pH 7.5) balanced salts solution of [125I] human BPI to E. coli J5 in the presence and absence of other human PMN granule proteins. BPI binding is saturable with an apparent K = 23 nM and 2.2 million binding sites/cell. While binding of [125I] human BPI is competitively inhibited by human or rabbit BPI, it is only weakly inhibited by myeloperoxidase, lysozyme, or cathepsin G. In contrast, myeloperoxidase binding to E. coli is strongly inhibited by BPI. Moreover, incubation of E. coli with crude extracts of PMN or CML spleen results in near quantitative binding of BPI, identified by silver staining and immunoblotting after SDS-PAGE of the washed E. coli pellet, without recognizable binding of other leukocyte proteins (greater than 98% of added total protein is recovered in supernatant). After addition of 200 mM MgCl2, approximately 80% of bound BPI is released as fully active and pure protein (as judged by SDS-PAGE and HPLC). Thus the selective and reversible binding of BPI in crude PMN extracts to target bacteria provides a one-step "affinity" purification procedure.
Antimicrobial Cationic Peptides↗
[Immune modulators in the treatment of malignant melanoma].
The experience gained to date with immunomodulators used as therapeutical and adjuvant measures in the treatment of cutaneous malignant melanoma is reviewed. In large studies no therapeutic effect has been shown for levamisole, DNCB and BCG preparations. The effectiveness of monoclonal antibodies, histamine type 2 receptor antagonists, thymus factors and mistletoe extracts cannot yet be assessed due to a lack of clinical studies. The recent use of the lymphokines: tumor-necrosis factor, interleukin 2 and interferons, has shown that tumor therapy with immunomodulators is possible, but many questions still remain to be answered, so that their use, especially as an adjuvant measure, should be restricted to controlled studies.
Adjuvants, Immunologic↗
The danger in skin grafting the bare mediastinum after sternectomy for postcoronary bypass dehiscence.
We describe a patient who underwent coronary bypass grafting, after which severe mediastinitis and sternal osteomyelitis occurred. Repair after sternectomy was undertaken with a rectus-abdominis myocutaneous flap. The distal fifth of the flap underwent necrosis and was replaced by a meshed split-thickness skin graft. A year later, a clip marking one of the bypass grafts nearly eroded through the skin graft, endangering the bypass graft. The skin graft was removed by abrasion, and the bypass graft was covered with a pectoralis muscle flap. We recommend that skin grafting of a granulating wound over coronary artery bypass grafts be avoided if possible.
Coronary Artery Bypass↗
Testosterone in a cyclodextrin-containing formulation: behavioral and physiological effects of episode-like pulses in rats.
Testosterone, administered in the form of an inclusion complex with 2-hydroxypropyl-beta-cyclodextrin by subcutaneous injection, enters the circulation in a manner markedly similar to the natural episodic release by the testes. The effects of a regimen of once-a-day administration of complexed testosterone to adult (castrated or intact) rats and to senescent (intact) rats were investigated. Although this procedure left the castrated animals with concentrations of circulatory hormone far below physiological levels for much of the day, a significant improvement in androgen-sensitive behavior and physiology was obtained. Furthermore, the testosterone effects were more pronounced when high doses were used periodically rather than when the same total amount of testosterone was equally divided among doses. The same supplementation to intact rats intensified androgen-sensitive behavior and physiology over normal levels. In senescent rats uniform pulses of the testosterone complex also improved behavior and physiology. Specifically, spermatogenesis was stimulated and, notably, the treatment increased muscle weight without substantial enlargement of the prostate. Since the testosterone-cyclodextrin complex also can be effectively administered as a sublingual tablet, the data suggest that similar regimens may be recommended for elderly men suffering from decreases in muscle mass.
Aggression↗