Successful immune reconstitution in severe combined immunodeficiency despite Epstein-Barr virus and cytomegalovirus infections

Cytomegalovirus (CMV) and Epstein-Barr virus (EBV), frequently found in the acquired immune deficiency syndrome (AIDS), have been suspected of contributing to the latter immunodeficiency. The ability of normal HLA-identical sibling bone marrow to reconstitute an 8-month-old infant with severe combined immunodeficiency infected with these two viral agents is of interest. After presentation with severe mucocutaneous candidiasis, cavitary pulmonary disease, nodular cutaneous lesions, and hepatic abscesses containing acid-fast organisms, immunologic studies revealed lymphopenia, 1-3% T cells, and no lymphocyte responses to mitogens. Prior to transplantation, the infant's blood B lymphocytes grew spontaneously in culture, suggesting they were infected with EBV. Indeed, an appropriate antibody response to EBV was detected at 2 months post-transplantation. At 3 weeks postgrafting, neutropenia and cholestatic jaundice developed without other signs of graft versus host disease. Liver biopsy demonstrated CMV but no EBV by DNA hybridization. There was evidence of T- and B-cell function by 2 weeks postgrafting, including vigorous in vivo and in vitro responses to candida. Although the blood lymphocyte T4:T8 ratio was inverted at 2 weeks, it reverted to normal by 6 weeks post-transplantation. All clinical disease resolved by 8 months and karotyping revealed all T and B lymphocytes to be XX. Thus, despite infections with both CMV and EBV, complete immunologic reconstitution was achieved in this, the most severe of all genetically determined immunodeficiency conditions, arguing against these viruses having a major role in the failure of bone marrow transplantation in AIDS.     

A Vicious Cycle of Osteosarcopenia in Inflammatory Bowel Diseases—Aetiology,Clinical Implications and Therapeutic Perspectives

Sarcopenia is a disorder characterized by a loss of muscle mass which leads to the reduction of muscle strength and a decrease in the quality and quantity of muscle. It was previously thought that sarcopenia was specific to ageing. However, sarcopenia may affect patients suffering from chronic diseases throughout their entire lives. A decreased mass of muscle and bone is common among patients with inflammatory bowel disease (IBD). Since sarcopenia and osteoporosis are closely linked, they should be diagnosed as mutual consequences of IBD. Additionally, multidirectional treatment of sarcopenia and osteoporosis including nutrition, physical activity, and pharmacotherapy should include both disorders, referred to as osteosarcopenia.     

Associations of Lifestyle Factors with Osteopenia and Osteoporosis in Polish Patients with Inflammatory Bowel Disease

Reduced physical activity (PA), smoking, and coffee and alcohol drinking constitute risk factors of osteoporosis in patients with inflammatory bowel disease (IBD). The aim of the study was to measure the bone mineral density (BMD) and frequency of osteopenia and osteoporosis in patients with IBD and their correlation with PA, smoking, coffee, and alcohol. The study group consisted of 208 patients with IBD-103 with Crohn’s disease (CD), 105 suffering from ulcerative colitis (UC). Densitometric measurements were performed using the DXA. All patients completed a questionnaire concerning PA, smoking, and coffee and alcohol consumption. The prevalence of osteopenia and osteoporosis (L2–L4) in the IBD group was 48.1%; in the CD group, it amounted to 48.6%, and in the UC group, the prevalence was equal to 33.3%. Patients with CD who were diagnosed with osteopenia and osteoporosis demonstrated reduced PA compared to patients with a normal BMD who exercised regularly (p = 0.0335). A similar observation was made in the group of women with IBD. Women with a normal BMD exercised significantly more often than women suffering from osteopenia and osteoporosis (p = 0.0146). However, no differences in BMD were observed with regard to coffee use, alcohol consumption, or smoking. Thus, since the incidence of osteoporosis in IBD patients is high, it may be dependent on PA.     

Correction to: How to support dental students in reading radiographs: effects of a gaze‑based compare‑and‑contrast intervention

Advances in Health Sciences Education -     

Spinal cord injury in the setting of traumatic thoracolumbar fracture is not reliably associated with increased risk of associated intra-abdominal injury following blunt trauma: An analysis of a National Trauma Registry database

Purpose: There is a common opinion that spinal fractures usually reflect the substantial impact of injuries and therefore may be used as a marker of significant associated injuries, specifically for intraabdominal injury (IAI). The impact of concomitant spinal cord injury (SCI) with the risk of associated IAI has not been well clarified. The aim of this study was to evaluate the incidence and severity of IAIs in patients suffering from spinal fractures with or without SCI. Methods: A retrospective cohort study using the Israeli National Trauma Registry was conducted. Patients with thoracic, lumbar and thoracolumbar fractures resulting from blunt mechanisms of injury from January 1, 1997 to December 31, 2018 were examined, comparing the incidence, severity and mortality of IAIs in patients with or without SCI. The collected variables included age, gender, mechanism of injury, incidence and severity of the concomitant IAIs and pelvic fractures, abbreviated injury scale, injury severity score, and mortality. Statistical analysis was performed using GraphPad InStat ® Version 3.10, with Chi-square test for independence and two sided Fisher’s exact probability test. Results: Review of the Israeli National Trauma Database revealed a total of 16,878 patients with spinal fractures. Combined thoracic and lumbar fractures were observed in 1272 patients (7.5%), isolated thoracic fractures in 4967 patients (29.4%) and isolated lumbar fractures in 10,639 patients (63.0%). The incidence of concomitant SCI was found in 4.95% (63/1272), 7.65% (380/4967) and 2.50% (266/10639) of these patients, respectively. The overall mortality was 2.5%, proving higher among isolated thoracic fracture patient than among isolated lumbar fracture counterparts (11.3% vs. 4.6%, p < 0.001). Isolated thoracic fractures with SCI were significantly more likely to die than non-SCI counterparts (8.2% vs. 3.1%, p < 0.001). There were no differences in the incidence of IAIs between patients with or without SCI following thoracolumbar fractures overall or in isolated thoracic fractures; although isolated lumbar fractures patients with SCI were more likely to have renal (3.4% vs. 1.6%, p = 0.02) or bowel injuries (2.3% vs. 1.0%, p = 0.04) than the non-SCI counterparts. Conclusion: SCI in the setting of thoracolumbar fracture does not appear to be a marker for associated IAI. However, in a subset of isolated lumbar fractures, SCI patient is associated with increased risks for renal and bowel injury.     

EEG effects of hallucinogens and cannabinoids using sleep-waking behavior as baseline

Three hallucinogens (d-lysergicacid diethylamide (LSD), mescaline, psilocybin) and two cannabinoid derivatives (tetrahydrocannabinol (THC), synhexyl) were tested for their long-term effects on the EEG of the cat. The drug-induced alterations in the EEG frequency spectrum were "drug-specific" in the sense that they would be statistically unlikely to occur during sleep-waking behavior. The two classes of compounds produced distinctly different EEG effects which were remarkably similar within each class. The duration of activity and relative potencies were consistent with those obtained by other measures, both in cats and in other species including man.     

A phase I trial of continuous-infusion cyclophosphamide in refractory cancer patients

Summary Cyclophosphamide demonstrates enhanced tumoricidal activity with decreased bone marrow toxicity when given on a divided-dose schedule in certain animal models. A total of 22 patients presenting with refractory metastatic cancer were treated in a phase I trial of continuous infusion of cyclophosphamide over 96 h. Granulocytopenia of <500/l that lasted for > 14 days or thrombocytopenia of <25,000/l that lasted for > 14 days was the target dose-limiting toxicity in the absence of nonhematologic grade 4 toxicity. The maximal tolerated dose was 7 g/m². Three patients died. Of 21 evaluable patients, 9 responded, including 8/9 who had experienced disease progression during prior oxazaphosphorine-containing combination chemotherapy. Clinically meaningful responses were observed in patients who had demonstrated clinical resistance to an oxazaphosphorine drug given at lower doses.Supported in part by U.S. Public Health Service grant P01CA-38493 and by a grant from the Mather's Foundation. Two of the authors (J. P. E. and A. D. E.) are recipients of Career Development awards from the American Cancer Society, and one (T. C. S.) is a recipient of a Faculty Development Award from the Pharmaceutical Manufacturer's Association Foundation     

Outward Currents in Rat Entorhinal Cortex Stellate Cells Studied with Conventional and Perforated Patch Recordings

We have studied outward currents of neurons acutely isolated from superficial layers of the entorhinal cortex with whole-cell patch-clamp recordings. If cells were held more negative than -50 mV, depolarizing voltage commands activated a transient A-type current together with a sustained outward current. Both currents were sensitive to 4-aminopyridine, while only the sustained current was blocked by tetraethylammonium. The sustained outward current showed a considerable rundown in amplitude over prolonged recording periods. At the same time its half-maximal inactivation shifted from -74 to -114 mV. Nystatin perforated patch recordings were used to minimize these perfusion effects. Under such conditions the amplitude and the steady-state inactivation properties of the sustained outward current remained stable for more than 1 h. Pharmacological investigations revealed that only a small part of the sustained outward current could be attributed to a calcium-activated potassium current. Therefore most of the rundown has to be due to changes in the delayed rectifier outward current. These results may suggest that the delayed rectifier current is under considerable metabolic control.     

Phase I clinical trial of the farnesyltransferase inhibitor BMS-214662 given as a 1-hour intravenous infusion in patients with advanced solid tumors.

PURPOSE: BMS-214662 is a nonsedating benzodiazepine derivative that exhibits broad spectrum cytotoxicity against human solid tumor cell lines and potently inhibits farnesylation of the H-ras and K-ras oncogenic proteins. This report describes the initial Phase I clinical trial of the compound. The main objective of the study was to determine the dose-limiting toxicities and the maximum tolerated dose of BMS-214662 when administered as a single dose i.v. over 1 h every 21 days to patients with advanced solid tumors. EXPERIMENTAL DESIGN: Patients with advanced solid tumors and adequate organ function were eligible for the study. The dose was escalated according to a modified Fibonacci schedule after evaluating groups of at least three patients for toxicity during the first cycle of therapy at each dose level. Pharmacokinetic and pharmacodynamic studies were performed after administration of the two initial doses. RESULTS: The dose of BMS-214662 was escalated from 36 to 225 mg/m(2) through 5 intermediate dose levels in a total of 44 patients. Dose-limiting toxicities occurred in 3 of the 13 (23%) patients during the first cycle of treatment with 225 mg/m(2), consisting of grade 3 nausea/vomiting in 2 patients and grade 3 diarrhea in another patient. In addition, four of these patients experienced reversible grade 3 transaminitis, which was not considered to be dose-limiting. At the recommended dose for Phase II studies, 200 mg/m(2), the most common side effects were reversible transaminitis, nausea, and vomiting. Although there were no objective responses, one patient with pancreatic cancer continues to receive treatment more than 3.5 years after entering the study. BMS-214662 exhibited linear pharmacokinetics and had a mean biological half-life of 1.55 +/- 0.27 h and a total body clearance of 21.8 +/- 10.8 liters/h/m(2), with a low apparent volume of distribution at steady state (31.5 +/- 12.9 liters/m(2)). In patients treated with the recommended Phase II dose, the mean maximum plasma concentration of the drug was 6.57 +/- 2.94 microg/ml, and farnesyltransferase activity in peripheral blood mononuclear cells decreased to a nadir of 10.5 +/- 6.4% of baseline at the end of the infusion but fully recovered within 24 h. CONCLUSIONS: BMS-214662 can be delivered safely as a single 1-h i.v. infusion at a dose that results in pronounced inhibition of farnesyltransferase activity in peripheral blood mononuclear cells. However, the duration of enzyme inhibition was transient, recovering in parallel with the decline in plasma concentrations of this rapidly eliminated drug. Because indications of anticancer activity were observed in several patients, further optimization of the administration schedule for this promising new compound is warranted.     

Plasma thyroxine and cholesterol concentrations of miniature pigs are influenced by thermally oxidized dietary lipids

To investigate the effect of a dietary oxidized oil on thyroid hormone status and circulating cholesterol, we conducted a study with 16 male miniature pigs fed a nutritionally adequate diet with 15% of either fresh or thermoxidized oil for 35 d (n = 8/group). The thermoxidized oil was prepared by heating sunflower oil at 110 degrees C for 48 h. The fresh oil consisted of a mixture of sunflower oil and lard (94:6, v/v) which had a fatty acid composition similar to the thermoxidized oil. At the end of the study, there were no differences in body weight gains and plasma clinicochemical variables between groups, suggesting that the thermoxidized oil did not induce general toxic symptoms. However, pigs fed the thermoxidized oil had significantly higher plasma concentrations of total and free thyroxine (P < 0.05) and a tendency for a higher plasma concentration of thyroid hormone-stimulating hormone (P < 0.1) than pigs fed the fresh oil. Additionally, pigs fed the thermoxidized oil had lower concentrations of cholesterol in plasma, LDL and HDL (P < 0.05). There were significant negative correlations between the plasma concentrations of total (r = -0.29) and free thyroxine (r = -0.40) and that of cholesterol (P < 0.05), suggesting that there is a causal relationship between the changes in thyroxine concentration and the reduction of plasma cholesterol. Our results indicate that there is a close relationship between alterations of thyroid hormone status and cholesterol metabolism in pigs fed a thermoxidized oil, and dietary oxidized fats should be considered in thyroid hormone disorders.