An inhibitor of cytotoxic functions produced by CD8+CD57+ T lymphocytes from patients suffering from AIDS and immunosuppressed bone marrow recipients

An inhibitor of the cytotoxic functions (ICF) mediated by human immunodeficiency virus (HIV)- or HLA-specific cytotoxic T lymphocytes, natural killer and lymphokine-activated killer (LAK) cells is secreted by CD8⁺CD57^? T lymphocytes, a subset expanded during infection with HIV and after bone marrow transplantation. We previously showed an apparent molecular mass of 20–30 kDa for this soluble glycosylated concanavalin A-binding inhibitor which is distinct from known cytokines. Here, we report a characterization of the mechanism of action of this CD8⁺CD57⁺ ICF. We show that the ICF-induced inhibition of LAK cell cytolytic activity is transient, with a spontaneous recovery of cytolytic potential after 18 h. When testing interactions of ICF with a large set of cytokines we found that the ICF-mediated inhibition of cytotoxic functions is antagonized by two cytokines: recombinant interleukin (rIL)-4 and recombinant interferon (rIFN)-γ. Finally, we show that ICF acts at the level of cytolytic effector cells, where it induces a significant increase of cyclic AMP (cAMP) level. In contrast, no modification of either cell surface antigen expression or of target/effector cell conjugate formation could be evidenced. Addition of rIL-4 and rIFN-γ reverses such an increase of cAMP levels and in parallel restores the cytolytic activity. Altogether, these data demonstrate that the glycoprotein ICF produced by CD8⁺CD57⁺ cells (1) inhibits cell-mediated cytotoxicity by sensitizing cytolytic effector cells to the cAMP pathway, and (2) is part of a cytokine network controlling cell-mediated cytotoxic functions.     

Synaptophysin in spinal anterior horn in aging and ALS: an immunohistological study

Summary Aged-related spinal cord changes such as neuronal loss have been related to the degree of clinical severity of amyotrophic lateral sclerosis (ALS); morphological data on synapses are, however, wanting. Variations in synaptophysin (Sph) expression in aging and ALS were thus studied at the level of lower motor neurons in 40 controls with non-neurological diseases and 11 cases of ALS. Control sections of formalin fixed paraffin embedded cervical (C7/8), thoracic (T10) and lumbar spinal cord (L5) and C6, C7, C8 and L5 of ALS cases were stained with haematoxylin and eosin, luxol fast blue (LFB), and immunostained with a mouse monoclonal antibody against Sph. The neuropil of the anterior horn (AH) in all control cases demonstrated Sph positivity. A dot-like pattern of positivity of presynaptic terminals on soma of motor neurons and fine immunoreactivity along neuronal processes were observed. A significant reduction of Sph immunostaining was observed in the neuropil with increasing age and 3 different somatic patterns were seen: a-well preserved Sph reactivity around the soma and the proximal dendrites of histologically normal neurons; b-few chromatolytic neurons showing large numbers of dot-like presynaptic terminals around the cell body and in a fused pattern; c-intense, diffuse, and homogeneous reactivity of some neurons. Attenuation of Sph reactivity in the AH neuropil, to its complete loss, was observed in all ALS cases. In addition to patterns a-c, two additional microscopic findings were noted in ALS: d-chromatolytic neurons showing complete absence of Sph reactivity; e-absence of Sph reactivity around the soma and the proximal dendrites of histologically normal surviving neurons.Our findings demonstrate that there is a decrease in Sph immunostaining with aging, thus suggesting an alteration in dendritic networks of the AH with aging. Changes in the pattern of Sph immunoreactivity in cell bodies may represent synaptic plasticity and/or degeneration. Reinnervation may also be a possible mechanism as a response to neuronal loss in oldest control cases. Sph reactivity results may thus lend support to the presence of superimposed aging components in ALS cases which may give an insight into explaining the increasing severity of the disease which is encountered with advancing age.     

Knochenheilung und dynamischer Interferenzstrom (DIC). —Erste vergleichende tierexperimentelle Studie an Schafen Teil II: Physikalische und chemische Ergebnisse

Zusammenfassung Zusätzlich wurden physikalische und chemische Untersuchungen über den Einfluß von dynamischem Interferenzstrom (DIC) auf die Knochenheilung durchgeführt, nachdem bei 24 Schwarzkopfschafen eine Querosteotomie des Radius vorgenommen worden war. Nach instabiler Osteosynthese wurde die Osteotomiezone wiederholt mit DIC verschiedener mA—Stärken behandelt. (Methodische Einzelheiten sind in Teil I beschrieben). Die Behandlung mit dynamischem Interferenzstrom führte im behandelten Gewebe zu steigenden Temperaturen, die von den mA—Stärken abhängig waren. Weiterhin wurden Zusammenhänge zwischen DIC—mA—Intensität und dem Vorkommen von Hydroxyprolin, einer kollagenspezifischen Aminosäure, nachgewiesen, welches eine erhöhte Calcifizierungsaktivität zur Folge hatte. Messungen des Calcium— und Phosphorgehaltes im neugebildeten Knochengewebe wiesen bei den mit DIC behandelten Tieren vollständige Mineralisation zu einem viel früheren Zeitpunkt als bei den unbehandelten, nach gleichem Verfahren operierten Kontrolltieren auf. Ob DIC einen spezifischen Reiz auf die Knochenneubildung heilender Knochen ausübt, ist noch nicht vollständig geklärt.

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Bone healing and Dynamic Interferential Current (DIC)

Summary In the course of supplementary physical and chemical investigations of the influence ofDynamicInterferential Current (DIC) on bone healing 24 black-head sheep were subjected to transversal osteotomy of the radius. After an instable osteosynthesis the site was exposed to repeated therapy with DIC of varying mA intensity. (Methodological details are described in part 1.) DIC therapy resulted in altering the temperatures in the treated tissue, dependent on the mA intensity. Further associations were verified between DIC intensity and the occurrence of hydroxyprolin, an amino acid specific collagen, which also reflected increased calcifying activity. Measurements of the calcium and phosphorus levels in the regenerated (newly forming) bone tissue documented full mineralization in the DIC-treated animals at a much earlier date than in the untreated controls that had undergone similar operations. Whether DIC specifically stimulates osteogenesis within healing bones is still unclear.

     

Longitudinal neurological follow-up of a group of HIV-seropositive and HIV-seronegative hemophiliacs: results from the hemophilia growth and development study

BACKGROUND: Boys and young men with hemophilia treated with factor infusions before 1985 had a substantial risk of acquiring the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome. This study was designed to assess the effects of HIV and hemophilia per se on neurological function in a large cohort of subjects with hemophilia, and to investigate the relationships between neurological disease and death during follow-up. METHODS: Three hundred thirty-three boys and young men (207 HIV seropositive and 126 HIV seronegative) were evaluated longitudinally in a multicenter, multidisciplinary study. Neurological history and examination were conducted at baseline and annually for 4 years. The relationship between neurological variables, HIV serostatus, CD4+ cell counts, and vital status at the conclusion of the study was examined using logistic regression models. RESULTS: The risks of nonhemophilia-associated muscle atrophy, behavior change, and gait disturbance increased with time in immune compromised HIV-seropositive subjects compared with HIV seronegative or immunologically stable HIV-seropositive subjects. The risk of behavior change in immune compromised HIV-seropositive hemophiliacs, for example, rose to 60% by year 4 versus 10% to 17% for the other study groups. Forty-five subjects (13.5%), all of whom were HIV seropositive, died by year 4. Subjects who died had had increased risks of hyperreflexia, nonhemophilia-associated muscle atrophy, and behavior change. CONCLUSIONS: These results indicate that immune compromised, HIV-seropositive hemophiliacs have high rates of neurological abnormalities over time and that neurological abnormalities were common among subjects who later died. By contrast, immunologically stable HIV-seropositive subjects did not differ from the HIV-seronegative participants. Hemophilia per se was associated with progressive abnormalities of gait, coordination, and motor function.     

New Drugs for Chronic Myelogenous Leukemia

The introduction of tyrosine kinase inhibitors (TKIs) has changed the landscape of therapy for chronic myelogenous leukemia (CML). Once considered an incurable malignancy, CML now has become a manageable chronic condition. Despite the great advances that imatinib has brought to the treatment of CML, some patients still develop resistance to imatinib and other TKIs, such as dasatinib and nilotinib. Furthermore, none of the clinically available TKIs is capable of eradicating leukemia stem cells and therefore curing CML. Several new compounds have been developed in recent years in an attempt to manage TKI-resistant CML. These include third-generation TKIs (ponatinib, danusertib) and even old compounds such as omacetaxine, which were developed before imatinib and now find a possible niche in the treatment of imatinib-resistant CML. We review the current preclinical and clinical data on the most promising new compounds for the treatment of CML.     

A multi-centre,randomised, double-blind,placebo-controlled clinical trial of methylphenidate in the initial treatment of acute mania (MEMAP study)

Based on many clinical and preclinical findings the ‘vigilance regulation model of mania’ postulates that an unstable regulation of wakefulness is a pathogenetic factor in both mania and Attention Deficit Hyperactivity Disorder (ADHD) and induces hyperactivity and sensation seeking as an autoregulatory attempt to stabilize wakefulness. Accordingly, stimulant medications with their vigilance stabilizing properties could have rapid antimanic effects similar to their beneficial effects in ADHD. The MEMAP study – a multi-center, double-blind, placebo-controlled and randomized clinical trial (RCT) – assessed the antimanic efficacy and safety of a 2.5-day treatment with methylphenidate (20–40 mg/day). Of 157 screened patients with acute mania, 42 were randomly assigned to receive 20–40 mg per day of methylphenidate in one or two applications, or placebo. The primary outcome was the change in Young Mania Rating Scale (YMRS) sum scores from baseline to day 2.5 in the methylphenidate group compared to the placebo group. A group sequential design was chosen to justify early RCT termination based on efficacy or futility at an interim analysis after inclusion of 40 patients. In the interim analysis, the change from baseline in the YMRS total score at day 2.5 was not significantly different between both groups (F(1,37)=0.23; p=0.64). Thus, futility was declared for methylphenidate and the RCT was stopped. In summary, although methylphenidate was well tolerated and safe in the full analysis set, it failed to show efficacy in the treatment of acute mania. Trial registration: clinicaltrials.gov (URL: http://www.clinicaltrials.gov; registration number: NCT01541605).     

Comparison of breath-guards and face-masks on droplet spread in eye clinics

IntroductionCOVID-19 has impacted ophthalmic care delivery, with many units closed and several ophthalmologists catching COVID-19. Understanding droplet spread in clinical and training settings is paramount in maintaining productivity, while keeping patients and practitioners safe.ObjectivesWe aimed to assess the effectiveness of a breath-guard and a face mask in reducing droplet spread within an eye clinic.MethodsWe performed a randomised trial of droplet spread using a fluorescein-based cough model to assess the efficacy of a ‘breath-guard’ and ‘face-mask’ to prevent the spread of droplets. The ‘cough’ spray was collected on calibrated paper targets. The sheets were photographed under blue light, with an orange filter on the camera; the position and size of the spots was measured with software originally developed for astronomy.We performed 44 randomised coughs; 22 controls with no breath-guard or face-mask, 11 using breath-guard only and 11 with combined breath-guard and face-mask. We compared both the number of droplets detected and the area of drops on paper targets.ResultsThe average number of droplets in the controls was 19,430 (SE 2691), the breath-guard group 80 (SE 19) droplets (P < 0.001); in the combined In the group the count was 5 (SE 2), a significant drop from shield only (P = 0.008). The mean areas of each target covered by spots for each group were 5.7 ± 0.857% (95% CI), 0.004 ± 0.000104% (95% CI) and 0.001 ± 0.0000627% (95% CI) respectively.ConclusionThese results show that the breath-guard alone reduced the droplet count by 99.93%. Combining the breath-guard with a face-mask reduced the droplet count by over 99.98%. Breath-guards are widely used in clinics and this trial demonstrates that breath-guards with face-masks effectively block droplet spray.Subject terms: Risk factors, Microbiology