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Reemergence and extinction of self-injurious escape behavior during stimulus (instructional) fading.

Based on results of a functional analysis indicating that the self-injurious behavior (SIB) of 3 individuals was maintained by negative reinforcement (escape from instructional situations), the effects of stimulus (instructional) fading were evaluated in a multiple baseline design across subjects. The rate of instructions was reduced to zero at the beginning of treatment and was gradually increased (faded in) across sessions as long as SIB remained low. However, if SIB remained high for 10 consecutive sessions, extinction was implemented until SIB decreased, at which point extinction was withdrawn and fading was resumed. Treatment was completed when the rate of instructions was the same as in baseline (two per minute), and SIB remained below 0.5 responses per minute for two consecutive sessions. Results showed that instructional fading (without extinction) virtually eliminated SIB initially, but these effects were not maintained. All 3 subjects required multiple exposures to extinction and over 150 treatment sessions in order to meet the end-of-treatment criteria. Advantages and limitations of fading procedures without an extinction component, as well as extensions of both interventions to other clinical problems, are discussed.

Adult↗

Hydrogen peroxide inhibits glucose metabolism and collagen synthesis in bone.

Effects of H2O2 on bone were evaluated in an organ culture system. Tibiae from chick embryos were incubated for up to 3 days in culture medium containing 0.07 to 20 mM H2O2. Glucose metabolism was monitored by measuring lactate production and oxygen consumption, and collagen synthesis was determined by hydroxylation of proline. In addition to markedly inhibiting these parameters, H2O2 also decreased bone weight and alkaline phosphatase activity. Multiple exposures to H2O2 were somewhat more effective than a single exposure. Since H2O2 inhibits bone at low concentrations in vitro, the results suggest that the potential for harmful effects of H2O2 in the oral cavity should be investigated.

Animals↗

Cross-reactivity to metal compounds studied in guinea pigs induced with chromate or cobalt.

Multiple sensitivity to metals is often seen in humans. This may be due to cross-reactivity or to multiple sensitization. The pattern of cross-reactivity to some metal compounds was studied, using the guinea pig maximization test method. Animals were induced with K2Cr2O7 and CoCl2, respectively, and then challenged with K2Cr2O7, CoCl2, NiSO4, PdCl2 and RhCl3. No simultaneous reactivity was recorded. This supports the view that simultaneous reactivity in patients to nickel-cobalt and to chromate-cobalt is due to multiple exposure and sensitization, and not to cross-reactivity. The purity of the test compounds was analysed.

Animals↗

Effects of shaking and centrifugation on human sperm motility.

Fresh seminal specimens from 48 normospermic donors were subjected to shaking and centrifugation at various intensities and durations, and their effect on sperm motility was determined objectively by the multiple exposure photography (MEP) method. Shaking for 15 sec by mechanical vibrator did not induce any drop in serum percentage of motility, while shaking for 30 to 180 sec was followed by immediate drop of this parameter. Sperm velocity increased for a short duration in all shaken specimens, after which it dropped considerably in most cases. Following centrifugation below 330 g for 10-20 min, sperm motility was almost unaffected. However, there was a significant drop in sperm motility after specimens were subjected to rates above 580 g for the same time duration. Intensive shaking and centrifugation significantly increased the percentage of dead spermatozoa, as confirmed from the combined supravital staining and MEP technique.

Centrifugation↗

Rapid microcomputer-based analysis of semen characteristics from photographs taken by the MEP method.

Use of a microcomputer with the multiple exposure photography (MEP) method for rapid analysis of semen characteristics is described. The computer is programmed to calculate information fed from a digitizing tablet while scanning projected images of photographed sperm. In this way sperm concentration, percentage of motility, average velocity and frequency distribution of sperm velocity, as well as percentage of abnormal forms are immediately obtained. The method was found to be as accurate, less prone to error, and significantly less time consuming than the previous manual measuring method. It can greatly facilitate routine semen analysis in laboratories using the MEP method.

Computers↗

Effect of ace-inhibitors, calmodulin antagonists, acetylcholine receptor blocking, and alpha receptor blocking agents on motility of human sperm.

The purpose of this study was to investigate the influence of several pharmacological compounds on the motility and velocity of washed human spermatozoa. Results were evaluated by multiple exposure photography and computer-aided picture analysis. The motility-inhibiting effect of the antifertility drug gossypol was confirmed. Gossypol proved to be a potent inhibitor of the angiotensin converting enzyme (ACE) detectable in high concentrations in seminal plasma. However, human sperm motility was not inhibited during incubation with two other specific ACE-inhibitors (captopril, enalapril). On the contrary, high concentrations of captopril even showed a slight motility-stimulating effect. These results indicate no direct involvement of ACE in the regulation of sperm motility but suggest a direct interaction of gossypol with the plasma membrane of spermatozoa. To clarify whether or not gossypol blocks membranous ion transport, the effect of well-defined ion transport blocking agents on sperm motility was investigated. It was determined that the acetylcholine receptor blocker alpha-bungarotoxin and trifluoperazine, a specific calmodulin antagonist, inhibit sperm motility completely. Since stimulation of sperm motility by captopril may be due to an alpha-mimetic action of this compound, the influence of two alpha receptor blockers (bromocriptine, lisuride) on sperm motility was studied. Although lisuride inhibited sperm motility completely, bromocriptine revealed no influence. A temporary and reversible intervention with membrane transport processes could be a suitable way to regulate human sperm motility and male fertility.

Adrenergic alpha-Antagonists↗

Use of a sealed mini-chamber to investigate human sperm motility in real time under aerobic and anaerobic conditions.

To study the correlation between metabolism and motility, ejaculated human spermatozoa were washed in media containing glucose, pyruvate, and deoxyglucose in various combinations. Spermatozoa suspended in these media were incubated in sealed mini-chambers and subjected to aerobic or anaerobic conditions at 37 degrees C. The effect on the patterns of sperm motility was investigated in real time by direct observation and objective determination with the multiple exposure photography (MEP) method. The motility of spermatozoa incubated in media containing excess of glucose showed similar changes of motility quality with time, whether exposed to aerobic or anaerobic conditions, and in both cases motility lasted about 13 h. Motility of sperm incubated with pyruvate only was of a much lower quality, especially under anaerobic conditions, and in both circumstances lasted about 7 h. When glycolysis of fructose remnants was totally inhibited by deoxyglucose and sperm were incubated with pyruvate only, motility lasted for 2 h under aerobic conditions and only for about 1 h under anaerobic conditions. It is concluded that the main metabolic process that supplies energy for sperm motility is glycolysis, under both aerobic and anaerobic conditions. Oxidative respiration was less efficient as a source of energy for sperm motility. When glycolysis was inhibited and oxidative respiration was eliminated under anaerobic conditions, sperm motility lasted only for about 1 h, probably by using intracellular energy reserves.

Aerobiosis↗

Auditory frequency discrimination in adult developmental dyslexics.

Developmental dyslexics reportedly discriminate auditory frequency poorly. A recent study found no such deficit. Unlike its predecessors, however, it employed multiple exposures per trial to the standard stimulus. To investigate whether this affects frequency discrimination in dyslexics, a traditional two-interval same-different paradigm (2I_1A_X) and a variant with six A-stimuli per trial (2I_6A_X) were used here. Frequency varied around 500 Hz; interstimulus interval (ISI) ranged between 0 and 1,000 msec. Under 2I_1A_X, dyslexics always had larger just noticeable differences (JNDs) than did controls. Dyslexic and control JNDs were equal at shorter ISIs under 2I_6A_X, but dyslexics became worse than controls at longer ISIs. Signal detection analysis suggests that both sensory variance and trace variance are larger in dyslexics than in controls.

Adult↗

Cytochrome P4502D6(193-212): a new immunodominant epitope and target of virus/self cross-reactivity in liver kidney microsomal autoantibody type 1-positive liver disease.

Cytochrome P4502D6 (CYP2D6), target of liver kidney microsomal autoantibody type 1 (LKM1), characterizes autoimmune hepatitis type 2 (AIH2) but is also found in patients with chronic hepatitis C virus (HCV) infection. To provide a complete linear epitope B cell map of CYP2D6, we tested peptides spanning the entire sequence of CYP2D6. In addition to confirming previously described antigenic sites, we identified four new epitopes (193-212, 238-257, 268-287, and 478-497). CYP2D6(193-212) is immunodominant and was the target of 12 of 13 (93%) patients with AIH2 and 5 of 10 (50%) HCV/LKM1-positive patients. Because LKM1 is present in both AIH2 and a viral infection, we tested whether Abs to CYP2D6(193-212) arise through cross-reactive immunity between virus and self. We identified a hexameric sequence "RLLDLA" sharing 5 of 6 aa with "RLLDLS" of HCV(2985-2990) and all 6 aa with CMV(130-135). Of 17 CYP2D6(193-212)-reactive sera, 11 (7 AIH and 4 HCV) reacted by ELISA with the HCV homologue, 8 (5 AIH and 3 HCV) with the CMV homologue, and 8 (5 AIH and 3 HCV) showed double reactivity. Autoantibody binding to CYP2D6(193-212) was inhibited by preincubation with HCV(2977-2996) or CMV(121-140). Recombinant HCV-nonstructural protein 5 and CMV-UL98 proteins also inhibited Ab binding to CYP2D6(193-212). Affinity-purified CYP2D6(193-212)-specific Ab inhibited the metabolic activity of CYP2D6. The demonstrated similarity and cross-reactivity between CYP2D6(193-212) and two unrelated viruses suggests that multiple exposure to viruses mimicking self may represent an important pathway to the development of autoimmunity.

Adolescent↗

Inheritance pattern of mutant human immunodeficiency virus type 1 coreceptor gene CCR5 in an Indian family.

The most common form of mutation found in the CCR5 gene has been the precise 32-base pair (bp) deletion in the region corresponding to second extracellular loop of the chemokine receptor CCR5. Individuals homozygous for the delta 32 allele of CCR5 usually remain uninfected despite multiple exposures to HIV, whereas heterozygous individuals support less virus replication and show slower progression of the disease. This mutant allele in either homozygous or heterozygous form is quite common in white people of European heritage. Earlier work involving large populations of Asians and Africans failed to detect the presence of this mutant allele. We screened 145 normal unrelated healthy Indians and found one person who was heterozygous for the delta 32 allele of CCR5. We studied the inheritance of this deleted allele in this person's family. One parent, one of two sons, and the only daughter possessed this mutant allele. We cloned the entire coding region of wild-type and mutant alleles of CCR5 gene from the heterozygous individual mentioned and studied its coreceptor functions. The mutant allele had only a moderate interfering effect on coreceptor activity of the wild-type CCR5 allele in a cell fusion assay. We also report an improved method of genotyping CCR5 gene in this communication.

Alleles↗

Direct injection of liposome-encapsulated doxorubicin optimizes chemomyectomy in rabbit eyelid.

PURPOSE: Doxorubicin chemomyectomy presently represents the only permanent, nonsurgical treatment for blepharospasm and hemifacial spasm. The major deterrent to an otherwise extremely effective treatment protocol is the development in patients of localized inflammation, discomfort, and skin injury over the injection site. As a potential alternative therapy, Doxil (Sequus, Menlo Park, CA), a liposome-encapsulated form of doxorubicin that displays tissue-selective therapeutic effects compared with free doxorubicin, was examined. These effects have been related to its increased retention in tissues and its sustained release over time. For the skin, Doxil is classified as an irritant rather than a vesicant. METHODS: Rabbits received direct injections of 1, 2, or 3 mg Doxil alone or in sequence with other agents directly into the lower eyelids. The treated eyelids were examined daily for signs of skin injury. One month after the last injection, the rabbits were euthanatized, and their eyelids were examined histologically for the effect of Doxil on the orbicularis oculi muscle and the skin. RESULTS: At equivalent milligram doses of free doxorubicin, Doxil spared the skin from injury. Doxil was only approximately 60% as effective in killing muscles as the same milligram dose of free doxorubicin. However, either two injections of Doxil spaced 2 months apart or preinjury of the lid with bupivacaine before a single dose of Doxil treatment resulted in increased muscle loss compared with a single dose of Doxil alone and was as effective as free doxorubicin. Higher doses of Doxil did not increase the desired myotoxic effect; apparently, the dose effect levels off at a maximum. Signs of skin injury were minimal; there were small or no adverse skin changes at the maximum effective myotoxic doses. CONCLUSIONS: Injection of Doxil resulted in significant reduction of skin injury compared with doxorubicin alone. Although single injections of Doxil were myotoxic, multiple exposure of the eyelid to the liposome-encapsulated form substantially improved myotoxicity while sparing the skin. Repeated doses of the liposome-encapsulated form of doxorubicin may be as clinically effective as free doxorubicin injections and may produce fewer unwanted side effects.

Animals↗

Management of sports-related root fractures.

Fractures that occur midroot are most frequently missed in radiographs unless multiple exposures at different angles are used for diagnosis. Immediate treatment consists of reduction of the fracture with close apposition of segments and rigid splinting for 3 months. Because of the good potential for healing, root canal therapy is delayed until evidence of pulpal necrosis is confirmed. Healing is by hard tissue, connective tissue, bone, or a combination of these accompanied by obliteration of the root canal.

Athletic Injuries↗

Environmental medicine, part 4: pesticides - biologically persistent and ubiquitous toxins.

Although the use of pesticides has doubled every ten years since 1945, pest damage to crops is more prevalent now than it was then. Many pests are now pesticide resistant due to the ubiquitous presence of pesticides in our environment. Chlorinated pesticide residues are present in the air, soil, and water, with a concomitant presence in humans. Organophosphate and carbamate pesticides - the compounds comprising the bulk of current pesticide use - are carried around the globe on air currents. Municipalities, schools, churches, business offices, apartment buildings, grocery stores, and homeowners use pesticides on a regular basis. Pesticides are neurotoxins that can cause acute symptoms as well as chronic effects from repeated low-dose exposure. These compounds can also adversely affect the immune system, causing cell-mediated immune deficiency, allergy, and autoimmune states. Certain cancers are also associated with pesticide exposure. Multiple endocrine effects, which can alter reproduction and stress-handling capacity, can also be found. Limited testing is available to assess the toxic overload of these compounds, including serum pesticide levels and immune system parameters. Treatment for acute or chronic effects of these toxins includes avoidance, supplementation, and possibly cleansing.

Adipose Tissue↗

Increased activator protein 1 activity as well as resistance to heat-induced radiosensitization, hydrogen peroxide, and cisplatin are inhibited by indomethacin in oxidative stress-resistant cells.

It has been established that tumor cells develop resistance to a variety of therapeutic agents after multiple exposures to these agents/drugs. Many of these therapeutic agents also appear to increase the activity of transcription factors, such as activator protein 1 (AP-1), believed to be involved in cellular responses to oxidative stress. Therefore, we hypothesized that cellular resistance to cancer therapeutic agents may involve the increased activity of transcription factors that govern resistance to oxidative stress, such as AP-1. To investigate this hypothesis, a previously characterized cisplatin, hyperthermia, and oxidative stress-resistant Chinese hamster fibroblast cell line, OC-14, was compared to the parental HA-1 cell line. Electrophoretic mobility shift and Western blot assays performed on extracts isolated from OC-14 cells demonstrated a 10-fold increase in constitutive AP-1 DNA-binding activity as well as increased constitutive c-Fos and c-Jun immunoreactive protein relative to HA-1 cells. Treatment of OC-14 cells with indomethacin inhibited constitutive increases in AP-1 DNA-binding activity and c-Fos/c-Jun-immunoreactive protein levels. Clonogenic survival assays demonstrated that pretreatment with indomethacin, at concentrations that inhibited AP-1 activity, significantly reduced the resistance of OC-14 cells to heat-induced radiosensitization, hydrogen peroxide, and cisplatin. These results demonstrate a relationship between increases in AP-1 DNA-binding activity and increased cellular resistance to cancer therapeutic agents and oxidative stress that is inhibited by indomethacin. These results support the hypothesis that inhibition of AP-1 activity with nonsteroidal anti-inflammatory drugs, such as indomethacin, may represent a useful adjuvant to cancer therapy.

Animals↗

Halothane-related hepatitis. A clinical study of twenty-six cases.

Twenty-six patients are described who had otherwise unexplained hepatitis after halothane anaesthesia. Twenty-four (92 per cent) had multiple exposures, and 11 (42 per cent) died. In eight patients a characteristic pattern of delayed postoperative pyrexia has been found. Obesity was common, but the clinical features and complications were those of any severe hepatitis. Obesity, early onset of jaundice after anaesthesia, and low thrombotest, were associated with a fatal outcome. None of those who were followed up after recovery developed clinical or biochemical evidence of chronic liver disease. The differential diagnosis of postoperative jaundice is discussed, and it is shown that halothane patients with hepatic encephalopathy are significantly older (25.4 plus or minus 11.6 years) than those referred to this unit with viral hepatitis of equal severity (34.1 plus or minus 16.4 years). Unexplained jaundice or delayed pyrexia after a previous administration of halothane should be a contraindication to its further use.

Adult↗

Influence of several uropathogenic microorganisms on human sperm motility parameters in vitro.

AIM: The effects of certain uropathogenic microorganisms (Neisseria gonorrhoeae, Staphylococcus aureus, Staphylococcus epidermidis and Mycobacterium tuberculosis) on human sperm motility characteristics were studied in vitro. METHODS: In 10 healthy fertile men, ejaculates were aseptically obtained by masturbation and with a swim-up technique, a sperm suspension of high motility and purity was obtained. Several uropathogenic bacteria were obtained from outpatients with genitourinary tract infections. The sperm suspension was incubated with the pathogens at a bacteria: sperm ratio of 50:1 at 37deg. The sperm mobility parameters were estimated with a computer-assisted sperm analyzer (CASA) provided with a multiple-exposure photography system (Madi Corp., Zhejiang, China). Measurements were carried out at 0, 2 and 4 hours of incubation. RESULTS: Staphylococcus aureus significantly decreased the sperm motility and viability, but Staphylococcus epidermidis, Mycobacterium tuberculosis and Neisseria gonorrhoeae did not. CONCLUSION: Staphylococcus aureus has an inhibitory effect on human sperm motility in vitro.

Gonorrhea↗

Myiasis due to Cordylobia anthropophaga in Zambia.

Dermal or subdermal myiasis due to larvae of the African tumbu fly Cordylobia anthropophaga is described from Zambia for the first time. Differential diagnosis from the closely allied C. rodhaini is considered. A patient presenting with the lesion on the penis is described. Multiple infection with different developmental stages is discussed in relation to multiple exposure or immunity. Many cases of myiasis may not reach the attention of medical personnel because of the tendency of the mature larvae to migrate out of the lesion which subsequently heals; traditional healers, to whom the condition has been known for long, also successfully extract the larvae.

Adolescent↗

[Prevention of skin complications from immunodepression in organ transplantation].

As skin diseases after organ transplantation are often disabling and sometimes lethal, it is essential to develop preventive measures. The group "Skin and organ transplantation" of the French Society of Dermatology concentrated one's efforts on skin carcinomas and Kaposis's sarcoma. Skin carcinomas are the most frequent tumors observed in transplant recipients. Many factors participate to their pathogenesis such as genetic, environmental and iatrogenic. Their prevalence is very high in elderly transplant recipients with fair complexion, long time of immunosuppression, long time of sun exposure, multiple keratoses and warts. Preventive measures consist educational training, sun avoidance and treatment of keratoses. Transplant recipients who develop Kaposi's disease are all infected with Human Herpes Virus 8 (HHV-8). HHV-8 promoinfection occurred frequently before transplantation. Cofactors involved in the development of Kaposi' sarcoma will be probably identified by the results of an ongoing national prospective study of kidney transplant recipients. Immunosuppressive therapy should be tapered to the lowest possible level compatible with allograft function.

Humans↗