Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma

CD19 chimeric antigen receptor T (CAR T)-cell therapy with axicabtagene ciloleucel (axi-cel) for relapsed or refractory (R/R) large B-cell lymphoma (LBCL) may lead to durable remissions, however, prolonged cytopenias and infections may occur. In this single center retrospective study of 85 patients, we characterized immune reconstitution and infections for patients remaining in remission after axi-cel for LBCL. Prolonged cytopenias (those occurring at or after day 30 following infusion) were common with ≥grade 3 neutropenia seen in 21 of 70 (30%) patients at day 30 and persisting in 3 of 31 (9.7%) patients at 1 year. B cells were undetectable in 30 of 34 (88.2%) patients at day 30, but were detected in 11 of 19 (57.9%) at 1 year. Median immunoglobulin G levels levels reached a nadir at day 180. By contrast, CD4 T cells decreased from baseline and were persistently low with a median CD4 count of 155 cells/mL at 1 year after axi-cel (n=19, range: 33– 269). In total, 23 of 85 (27.1%) patients received intravenous immunoglobulins after axi-cel, and 34 of 85 (40%) received granulocyte-colony stimulating factor. Infections in the first 30 days occurred in 31 of 85 (36.5%) patients, of which 11 of 85 (12.9%) required intravenous antibiotics or hospitalization (“severe”) and were associated with cytokine release syndrome, neurotoxicity, tocilizumab use, corticosteroid use, and bridging therapy on univariate analyses. After day 30, seven severe infections occurred, with no late deaths due to infection. Prolonged cytopenias are common following axi-cel therapy for LBCL and typically recover with time. Most patients experience profound and prolonged CD4 T-cell immunosuppression without severe infection.     

Characterization of visual manifestations and identification of risk factors for permanent vision loss in patients with giant cell arteritis

Clinical Rheumatology - Permanent vision loss (PVL) is a feared complication and a leading cause of morbidity in giant cell arteritis (GCA). The objective of this study is to describe visual...     

The use of recombinant tissue plasminogen activator in in acute ischemic stroke is associated with increased level of BDNF

Much concern was directed towards the crucial role of recombinant tissue plasminogen activator (rt-PA) in improving neuroplasticity in patients with acute ischemic stroke. The aim of the work to investigate the effect of treating patients with acute ischemic stroke with rt-PA, on the level of brain derived neurotrophic factor (BDNF) as a marker of neuroplasticity. This study was conducted on 47 patients presenting with acute ischemic stroke (during the first 4.5 h from stroke onset); 26 patients of them eligible for receiving rt-PA (patient group) and 21 patients having contraindications for treatment with rt-PA (control group). Neurological, radiological and laboratory assessment (including BDNF serum level) were done for both groups at stroke onset (before receiving rt-PA) and at day 7. There was a statistically significant increase in BDNF serum level from day 1 to day 7 in rt-PA treated patients in comparison to control group (P-value? 0.001). Serum level of BDNF is significantly higher at the onset of stroke in female patients and non-smokers than males or smokers (P-value?=?0.011, 0.01 respectively). There was no effect of either age, body mass index, hypertension, diabetes, drug abuse, past or family history of stroke, valvular heart diseases, atrial fibrillation, cardiomyopathy, ejection fraction, carotid atherosclerotic changes, lipid profile or uric acid, on BDNF serum level measured at the onset of stroke. Treatment of patients with acute ischemic stroke with rt-PA causes significant improvement in neuroplasticity through increasing BDNF serum level.

     

In schizophrenia,non-remitters and partial remitters to treatment with antipsychotics are qualitatively distinct classes with respect to neurocognitive deficits and neuro-immune biomarkers: results of soft independent modeling of class analogy

Around one third of schizophrenia patients are non-responders to antipsychotic therapy. The present study aimed to delineate the pathway-phenotypes of non-remitters (NRTT) and partial remitters (PRTT) to treatment with antipsychotics as defined using the Global Clinical Impression scales. We recruited 60 NRTT, 50 PRTT and 43 healthy controls and measured schizophrenia symptoms, neurocognitive tests, plasma CCL11, interleukin-(IL)-6, IL-10, Dickkopf protein 1 (DKK1), high mobility group box-1 protein (HMGB1), κ- and μ-opioid receptors (KOR and MOR, respectively), endomorphin-2 (EM-2), and β-endorphin. Soft independent modeling of class analogy (SIMCA) showed that NRTT and PRTT are significantly discriminated with a cross-validated accuracy of 94.7% and are qualitatively distinct classes using symptomatome, and neuro-immune-opioid-cognitome (NIOC) features as modeling variables. Moreover, a NIOC pathway phenotype discriminated PRTT from healthy controls with an accuracy of 100% indicating that PRTT and controls are two qualitative distinct classes. Using NIOC features as discriminatory variables in SIMCA showed that all PRTT were rejected as belonging to the normal control class and authenticated as belonging to their target class. In conclusion, a non-response to treatment can best be profiled using a SIMCA model constructed using symptomatome and NIOC features. A partial response should be delineated using SIMCA by authenticating patients as controls or PRTT instead of using scale-derived cut-off values or a number of scale items being rated mild or better. The results show that PRTT is characterized by an active NIOC pathway phenotype and that both NRTT and PRTT should be treated by targeting neuro-immune and opioid pathways.

     

Efficacy of ultrasonography-guided intra-articular steroid injection of the shoulder and excercising in patients with adhesive capsulitis: Glenohumeral versus subacromial approaches

Aim of the work

To evaluate the efficacy of intra-articular steroid injection of the shoulder joint with exercises in the management of patients with adhesive capsulitis and to compare glenohumeral (GH) versus subacromial subdeltoid (SASD) ultrasound-guided approaches.

Observations on cattle schistosomiasis in the Sudan, a study in comparative medicine. V. The effect of praziquantel therapy on naturally acquired resistance to Schistosoma bovis

Studies in the White Nile area of the Sudan have shown that Zebu cattle acquire a high degree of resistance to Schistosoma bovis as a result of repeated natural exposures without, however, being able to eliminate their populations of adult schistosomes, although these do show greatly suppressed fecundity. To test whether these adult worms are necessary for the maintenance of resistance we cured six "naturally resistant" cattle (TC group) with a double treatment of 25 mg/kg praziquantel and compared their response to a 70,000 cercariae challenge with groups of "naturally resistant" but untreated cattle (UC group) and with previously unexposed, challenged cattle (CC group). Challenge was carried out 7 weeks after the second dose of praziquantel. The results confirmed that untreated cattle are "naturally resistant" and also showed that resistance was not abrogated by cure of the naturally-acquired infections. Thus, fecal egg counts after challenge reached mean maxima of 2,432 eggs per gram (epg) in the CC, but only 5 epg and 28 epg in the TC and UC groups, respectively. Similarly, mean worm counts were 85% and 69% lower in the TC and UC groups, respectively, and mean tissue egg densities were reduced by 72-99%, and 56-80%. Histopathologically, the TC and UC groups were also far less affected than the CC. Effective praziquantel treatment does therefore not destroy naturally acquired resistance to S. bovis, and may benefit infected livestock even in the absence of transmission control. The situation in human schistosomiasis is less clear, but there are several epidemiological and experimental indications of a similar conclusion for S. mansoni.     

Serological studies in the elderly.

Sera from 108 elderly patients in psychiatric and general hospitals were tested for antibodies to seven viruses. Measles virus antibody levels were significantly higher in patients from the psychiatric hospital, regardless of diagnosis, than in those from other hospitals. Demented patients, regardless of their hospital, had significantly higher levels of antibody to adenovirus than control patients.     

Liver regeneration is not altered in patients with nonalcoholic steatohepatitis (NASH) when compared to chronic hepatitis C infection with similar grade of inflammation

Fatty infiltration is associated with an increased incidence of complications and mortality after liver resection and transplantation. The aim of this study was to document the regenerative response in patients with hepatic steatosis and mild inflammatory activity (NASH) and to identify potential levels of impaired regeneration. Ki-67 immunostaining was similar in patients with NASH (ages 44.6 ± 15 years, labeling index, 0.4 ± 0.3%) when compared to patients with chronic hepatitis C infection (ages 50.7 ± 17 years, labeling index; 0.4 ± 0.7%). The labeling index was not increased in patients with a higher level of inflammation, a higher level of fibrosis, and a higher level of fat in either study group. In conclusion, liver regeneration is not altered in patients with nonalcoholic steatohepatitis, suggesting that the delayed postoperative liver failure seen in these patients may be related to another mechanism.     

Multi-Step Regulation of Interferon Induction by Hepatitis C Virus

Acute hepatitis C virus (HCV) infection evokes several distinct innate immune responses in host, but the virus usually propagates by circumventing these responses. Although a replication intermediate double-stranded RNA is produced in infected cells, type I interferon (IFN) induction and immediate cell death are largely blocked in infected cells. In vitro studies suggested that type I and III IFNs are mainly produced in HCV-infected hepatocytes if the MAVS pathway is functional, and dysfunction of this pathway may lead to cellular permissiveness to HCV replication and production. Cellular immunity, including natural killer cell activation and antigen-specific CD8 T-cell proliferation, occurs following innate immune activation in response to HCV, but is often ineffective for eradication of HCV. Constitutive dsRNA stimulation differs in output from type I IFN therapy, which has been an authentic therapy for patients with HCV. Host innate immune responses to HCV RNA/proteins may be associated with progressive hepatic fibrosis and carcinogenesis once persistent HCV infection is established in opposition to the IFN system. Hence, innate RNA sensing exerts pivotal functions against HCV genome replication and host pathogenesis through modulation of the IFN system. Molecules participating in the RIG-I and Toll-like receptor 3 pathways are the main targets for HCV, disabling the anti-viral functions of these IFN-inducing molecules. We discuss the mechanisms that abolish type I and type III IFN production in HCV-infected cells, which may contribute to understanding the mechanism of virus persistence and resistance to the IFN therapy.     

Paleopathology of the juvenile Pharaoh Tutankhamun—90th anniversary of discovery

Modern paleopathology is a multidisciplinary field of research which involves archaeology, medicine and biology. The most common diseases of Ancient Egypt were traumatic injuries, malaria and tuberculosis. Exemplarily, an internistic and trauma surgery case of that time is reviewed: Pharaoh Tutankhamun (ca. 1330–1324 B.C.). Summarising all findings which have been collected between 1922 and 2010, including computed tomography and molecular pathology, a diversity of disease is verifiable: (1) chronic/degenerative diseases (mild kyphoscoliosis, pes planus and hypophalangism of the right foot, bone necrosis of metatarsal bones II–III of the left foot); (2) inflammatory disease (malaria tropica, verified by PCR analysis) and (3) acute trauma (complex fracture of the right knee shortly before death). The most likely cause of death is the severe acute knee fracture and/or the malaria, while a suspected eighteenth dynasty syndrome cannot be proven.