Psychedelic science in post-COVID-19 psychiatry.

The medium- to long-term consequences of COVID-19 are not yet known, though an increase in mental health problems are predicted. Multidisciplinary strategies across socio-economic and psychological levels may be needed to mitigate the mental health burden of COVID-19. Preliminary evidence from the rapidly progressing field of psychedelic science shows that psilocybin therapy offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and maladaptive habitual patterns of cognition and behaviour, notably depression, addiction and obsessive compulsive disorder. The COMPASS Pathways (COMPASS) phase 2b double-blind trial of psilocybin therapy in antidepressant-free, treatment-resistant depression (TRD) is underway to determine the safety, efficacy and optimal dose of psilocybin. Results from the Imperial College London Psilodep-RCT comparing the efficacy and mechanisms of action of psilocybin therapy to the selective serotonin reuptake inhibitor (SSRI) escitalopram will soon be published. However, the efficacy and safety of psilocybin therapy in conjunction with SSRIs in TRD is not yet known. An additional COMPASS study, with a centre in Dublin, will begin to address this question, with potential implications for the future delivery of psilocybin therapy. While at a relatively early stage of clinical development, and notwithstanding the immense challenges of COVID-19, psilocybin therapy has the potential to play an important therapeutic role for various psychiatric disorders in post-COVID-19 clinical psychiatry.

Acute steroid myopathy: a highly overlooked entity.

BACKGROUND: Myopathy in patients being treated with corticosteroids is known primarily among chronically treated patients or in critically ill and mechanically ventilated patients receiving corticosteroids, often in high doses. AIM: To highlight the entity of acute, early onset corticosteroid-treatment-associated myopathy and its characteristics. DESIGN AND METHODS: Reporting our experience with four patients and reviewing all published reports of myopathy developing ≤14 days of initiating corticosteroid-treatment. RESULTS: Acute corticosteroid myopathy (ASM) exists, though the syndrome appears to be rare. It is characterized by unpredictability and heterogeneity, sometimes developing within 1-3 days, after a single dose, which may not be high and administered by varied routes. Proximal limb muscle weakness is the most common form, but distal limb, bulbar and respiratory muscles may be involved. Steroid cessation often leads to improvement/resolution, but irreversibility may occur. CONCLUSIONS: A high index of suspicion for the possibility of ASM is necessary to ensure drug discontinuation and recovery. This is particularly true since the entity is not widely recognized and its symptoms are often erroneously interpreted as due to the patient's underlying disease.

CD84 mediates CLL-microenvironment interactions.

Chronic lymphocytic leukemia (CLL) is a malignant disease of small mature lymphocytes. Signals from the CLL microenvironment promote progression of the disease and induce drug resistance. This phenomenon is largely dependent on direct contact between the malignant B cells and stromal cells. CD84 belongs to the signaling lymphocyte activation molecule family of immunoreceptors, which self-associates, forming an orthogonal homophilic dimer. We therefore hypothesized that CD84 may bridge between CLL cells and their microenvironment, promoting cell survival. Our in vitro results show that CD84 expressed on CLL cells interact with CD84 expressed on cells in their microenvironment, inducing cell survival in both sides. Blocking CD84 in vitro and in vivo disrupt the interaction of CLL cells with their microenvironment, resulting in induced cell death. Thus, our findings suggest novel therapeutic strategies based on the blockade of this CD84-dependent survival pathway.

CD84 is a survival receptor for CLL cells.

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of CD5+ B lymphocytes in peripheral blood, lymphoid organs and bone marrow. The main feature of the disease is accumulation of the malignant cells due to decreased apoptosis. CD84 belongs to the signaling lymphocyte activating molecule family of immunoreceptors, and has an unknown function in CLL cells. Here, we show that the expression of CD84 is significantly elevated from the early stages of the disease, and is regulated by macrophage migration inhibitory factor and its receptor, CD74. Activation of cell surface CD84 initiates a signaling cascade that enhances CLL cell survival. Both downmodulation of CD84 expression and its immune-mediated blockade induce cell death in vitro and in vivo. In addition, analysis of samples derived from an on-going clinical trial, in which human subjects were treated with humanized anti-CD74 (milatuzumab), shows a decrease in CD84 messenger RNA and protein levels in milatuzumab-treated cells. This downregulation was correlated with reduction of Bcl-2 and Mcl-1 expression. Thus, our data show that overexpression of CD84 in CLL is an important survival mechanism that appears to be an early event in the pathogenesis of the disease. These findings suggest novel therapeutic strategies based on the blockade of this CD84-dependent survival pathway.

Physicians' attitudes towards self-treatment of latent tuberculosis.

We conducted a cross-sectional study to assess physicians' attitudes towards self-treatment of latent tuberculosis infection (LTBI) based on real-time responses related to actual purified protein derivative (PPD) results, in addition to using hypothetical situations for those who were PPD-negative. We also obtained information on physicians' recommendations for their patients to treat this condition. Although the physicians claimed to recommend optimal treatment to their patients, the majority of them had different attitudes when considering treatment for themselves. There appears to be a discrepancy between physicians' attitudes to self-treatment and their management of patients with LTBI.

The hazards of diagnosis.

BACKGROUND: Making a diagnosis is perceived as a climax of clinical effort. Little consideration is being given to potential down sides after the diagnosis is achieved. METHODS: The authors' personal experience, extensive discussions with peers and a search of the literature. RESULTS: Several common and significant pitfalls after making a diagnosis were identified. They include 'locking' and disregard of further data pointing to possible diagnostic error; pursuing a diagnosis when further information has little practical significance; a severe impact of the news on the patient; a 'stigma' effect; loss of the patient's individual narrative; stopping the diagnosis short of the full pathogenesis or of its finer characterization; disregarding additional medical issues; losing interest in the patients once the diagnostic problem is solved; and assuming full control of future decisions at the expense of the patient's autonomy. CONCLUSION: Physicians need to be cognizant of the impact and significant potential for harm associated with closure of diagnosis and its delivery to their patient. Humility, double-checking and sensitivity to the patient's predicament may improve quality and communication and prevent 'the hazards of diagnosis'.

Is it recurrent cryptococcal meningitis or immune reconstitution inflammatory syndrome?

We report a case of a 45-year-old patient with a history of cryptococcal meningitis who was started on antiretroviral therapy. The patient presented four months later with complaints of fever and memory loss. Lumbar puncture revealed positive cryptococcal antigen and therefore the patient was treated for recurrent cryptococcal meningitis. Unfortunately, the patient did not improve even after two weeks. The diagnosis of immune reconstitution was made at this time and steroids were started. The patient showed remarkable improvement.

The SF-36 walk-wheel: a simple modification of the SF-36 physical domain improves its responsiveness for measuring health status change in spinal cord injury.

OBJECTIVE: To evaluate the validity and responsiveness of a modified SF-36 within a spinal cord-injured (SCI) population. STUDY DESIGN: SF-36 scores collected at baseline and on completion of a randomized controlled trial in 305 patients with SCI and neuropathic bladder. SETTING: New South Wales, Australia. METHODS: Subjects were administered the standard SF-36 plus three additional questions, in which 'walk' was replaced with 'wheel' for three of the physical function (PF) questions. Discriminant validity was determined by comparing participants with paraplegia and tetraplegia using the effect size (ES). Responsiveness was assessed in the subset of patients who developed a urinary tract infection (UTI) during the trial using the standardized response mean (SRM). RESULTS: Compared with the standard SF-36, the SF-36 walk-wheel modification (SF-36ww) increased the mean PF score from 18 to 39 (P<0.001) and the physical composite score from 33 to 37 (P<0.001). Discriminant validity was similar for both versions (PF paraplegia/tetraplegia: ES 1.09(SF-36) vs 1.08(SF-36ww), n=305). Among 138 SCI patients who developed a UTI, the SF-36ww almost doubled PF responsiveness for all neurological levels (SRM increased from 0.36 to 0.68), more so in tetraplegic (SRM, 0.11 vs 0.58; n=77) than paraplegic groups (SRM, 0.77 vs 0.86; n=61). CONCLUSION: The SF-36ww is a simple, pragmatic modification of the SF-36 PF items, which addresses some problems of content validity and floor effect for SCI subjects and greatly improves responsiveness, particularly for those with tetraplegia. Because it comprises a simple addition to the standard SF-36, external comparisons are preserved.

Direct antiglobulin test reactive with complement only in warm type autoimmune hemolytic anemia.

Direct antiglobulin test (DAT) with only complement detected on red blood cells is a rare laboratory finding, and its significance in the setting of warm autoimmune hemolytic anemia (AIHA) is controversial. During 2 years (2003-2004) 277 patients with positive DAT were recorded in the blood bank registries, 17 of them had DAT reactive with C3 alone with no cold agglutinin or other nonimmune causes for hemolysis diagnosed. Red cell eluate disclosed small amounts of IgG in two patients. In nine patients no signs of clinical hemolysis were found, however, all these patients had underlying conditions that are known to be associated with red cells autoantibodies (autoimmune disorder or malignancy). Eight patients developed AIHA, seven of them with severe hemolysis. Three patients had idiopathic AIHA, and the others have been diagnosed with infectious, lymphoproliferative and autoimmune disorders. In two patients with acute infection the hemolytic process spontaneously resolved, three responded to corticosteroid therapy, while three patients were refractory to two lines of drug therapy and underwent splenectomy. Reticulocytopenia was found in four patients. Our results emphasize that AIHA with DAT reactive with complement alone is a rare disorder and might be accompanied by severe, refractory to conventional treatment and life-threatening hemolysis.

Spinal-injured neuropathic bladder antisepsis (SINBA) trial.

OBJECTIVE: To determine whether Methenamine Hippurate (MH) or cranberry tablets prevent urinary tract infections (UTI) in people with neuropathic bladder following spinal cord injury (SCI). STUDY DESIGN: Double-blind factorial-design randomized controlled trial (RCT) with 2 year recruitment period from November 2000 and 6 month follow-up. SETTING: In total, 543 eligible predominantly community dwelling patients were invited to participate in the study, of whom 305 (56%) agreed. METHODS: Eligible participants were people with SCI with neurogenic bladder and stable bladder management. All regimens were indistinguishable in appearance and taste. The dose of MH used was 1 g twice-daily. The dose of cranberry used was 800 mg twice-daily. The main outcome measure was the time to occurrence of a symptomatic UTI. RESULTS: Multivariate analysis revealed that patients randomized to MH did not have a significantly longer UTI-free period compared to placebo (HR 0.96, 95% CI: 0.68-1.35, P=0.75). Patients randomized to cranberry likewise did not have significantly longer UTI-free period compared to placebo (HR 0.93, 95% CI: 0.67-1.31, P=0.70). CONCLUSION: There is no benefit in the prevention of UTI from the addition of MH or cranberry tablets to the usual regimen of patients with neuropathic bladder following SCI.

Pharmacological interventions for treating acute heterotopic ossification.

BACKGROUND: Heterotopic ossification (HO) is the formation of mature lamellar bone in soft tissue sites outside the skeleton. HO frequently complicates burns, arthroplasty, fractures, and spinal cord and brain injuries. It can impair joint function. OBJECTIVES: To determine the efficacy of medications to treat acute HO on radiological, symptomatic, functional impairment, and disability outcomes. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Injuries Group specialised register, the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2004), MEDLINE (1966 to August 2004), EMBASE (1980 to August 2004), CINAHL (1982 to August 2004), other databases, reference lists of articles, and contacted trialists and drug companies. No language restrictions were applied. SELECTION CRITERIA: All randomised or quasi-randomised controlled trials that assessed the efficacy of any medication for treating acute HO (confirmed by bone scintigraphy, radiography, ultrasonography, or biopsy) and which used radiography to grade post-treatment HO severity. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the study quality and extracted data. We analysed two dichotomous outcomes: no progression in HO grade (versus progression) and improvement in HO grade (versus no improvement). MAIN RESULTS: Two randomised trials comparing disodium etidronate versus placebo were included (Ono 1988; Stover 1976), from which ninety-two participants with spinal cord injury had radiographically-proven HO at baseline. At the completion of the 12 week intervention, the Ono study but not the Stover study, suggested that disodium etidronate was associated with a significantly greater likelihood of successfully preventing the progression of radiographic HO grade, (relative risk (RR) 1.50; 95% confidence interval (CI) I 1.16 to 1.93; and RR 1.48; 95% CI 0.78 to 2.84 respectively) and a significantly greater likelihood of improvement in HO grade (RR 2.78; 95% CI 1.66 to 4.66; and RR 0.71; 95% CI 0.20 to 2.53 respectively). There was evidence of statistical heterogeneity for the latter outcome. Longer term radiographic, clinical or side effect outcomes were unavailable. Data was not pooled due to this heterogeneity and the inadequate duration of follow up. REVIEWERS' CONCLUSIONS: Given the absence of long term radiographic outcomes in the included studies, there is insufficient evidence to recommend the use of disodium etidronate or other pharmacological agents for the treatment of acute HO. It has been previously suggested that disodium etidronate acts by delaying, rather than preventing, the mineralization of HO, and that mineralization may occur after treatment cessation in many cases, thereby negating the benefit of disodium etidronate on eventual HO grade. Further studies are required to assess all pharmacological treatments for acute HO with sufficient follow-up duration.

Grb7 expression and cellular migration in chronic lymphocytic leukemia: a comparative study of early and advanced stage disease.

Grb7, a noncatalytic intracellular adaptor protein involved in cell migration, is overexpressed in certain invasive and metastatic solid tumors. We found a highly significant difference in the level of expression of Grb7 between chronic lymphocytic leukemia (CLL) cells obtained from stage I and stage IV patients (P<0.001). Using semiquantitative RT-PCR, we detected high levels of Grb7 in 88% of stage IV patients vs only 18% in stage I patients. A corresponding increase was found in the in vitro migration of stage IV CLL cells in comparison to stage I cells. The statistically significant difference in the expression of Grb7 between stage IV and stage I patients was preserved even when tested specifically in the ZAP70-positive group (P<0.01). These findings show that Grb7 levels reflect the severity of the disease, and may be used, in conjunction with ZAP70, to predict disease progression.

Successful treatment of aggressive HIV-associated non-Hodgkin's lymphoma with combination chemotherapy, biotherapy with rituximab and HAART: presentation of a therapeutic option.

The incidence of non-Hodgkin's lymphoma (NHL) in individuals infected with human immunodeficiency virus (HIV) is more than 60 times higher than in matched controls. In the vast majority of cases aggressive pathological subtypes and advanced stages prevail, extranodal sites are involved and systemic symptoms are present. The prognosis of HIV-NHL remains poor and the optimal therapeutic approach has yet to be defined. We report a 48-year-old Ethiopian woman with advanced-stage HIV infection, who developed diffuse large cell, immunoblastic type B-cell NHL and was treated with a modified CHOP-like chemotherapy combined with Rituximab and supported with growth factor. Highly active antiretroviral therapy (HAART) and opportunistic infections prophylaxis were administered concomitantly. The patient completed 6 cycles of therapy and currently, 76 weeks after diagnosis, is in complete clinical remission. Despite the fact that there was a transient decrease in the CD4-positive cell number and a 1.5 log increase in plasma viral load there were no opportunistic infections, nor was life-threatening toxicity seen. Rituximab seems a well-tolerable and advantageous adjunct to chemotherapy and HAART in the treatment of aggressive HIV-associated NHL andshould be investigated in large trials in the future.

Paraplegia secondary to Burkholderia pseudomallei myelitis: a case report.

Bacterial infection is an uncommon cause of acute paraplegia. A 42-year-old Aboriginal man presented to a remote health clinic in northern Australia with myelitis associated with Burkholderia pseudomallei. He was treated with analgesia and intravenous flucloxacillin, ceftriaxone, and gentamicin and transferred to our hospital, where an urgent T12-L1 laminectomy and decompression was performed. Urine culture confirmed B. pseudomallei infection (melioidosis). Abdominopelvic computed tomography revealed left prostatic lobe and right periprostatic abscesses, which were managed conservatively. The patient was given intravenous ceftazidime (8g/d) for 2 months, followed by oral sulfamethoxazole (1600mg) and trimethoprim (320mg) twice daily for 8 weeks. Magnetic resonance imaging 3 weeks after his admission confirmed transverse myelitis. His rehabilitation was complicated by his difficulty in adjusting to disability, by urinary retention and fecal incontinence, by communication barriers, and his isolation from a culture familiar to him. He returned to his community after 15 weeks, free of infection, with T10-11 paraplegia and an indwelling catheter.

Evidence that inhibition of cathepsin-B contributes to the neuroprotective properties of caspase inhibitor Tyr-Val-Ala-Asp-chloromethyl ketone.

During the use of tetrapeptide and other proprietary caspase inhibitors in the study of neurodegeneration, we had concluded that mechanisms other than the inhibition of caspases contributed to the protective effects of certain caspase inhibitors. Here we report our studies to identify a target for and hence a mechanism by which the tetrapeptide inhibitor tyrosine-valine-alanine-aspartate-chloromethyl ketone (Ac-YVAD-cmk) is able to rescue neuronal cell cultures from cell death. Ac-YVAD-cmk rescued neuronal cells from cell death in response to oxidative stress and oxygen/glucose deprivation. Affinity labeling with biotinylated YVAD-cmk demonstrated distinct binding proteins for the inhibitor in cells from the central nervous system versus Jurkat cells. Binding to the novel target protein was displaced by class-specific protease inhibitors and suggested that the target is a cysteine protease. Affinity purification and sequencing identified the target as cathepsin-B. Cathepsin-B inhibitors competed with biotinylated YVAD-cmk for the target protein. The availability of the target for binding was reduced in cells that had been rescued by unlabeled inhibitor. Cathepsin-B inhibitors rescue hippocampal slices from cell death induced by oxygen/glucose deprivation. These data provide evidence to support a role for cathepsin-B in neuronal cell death, particularly that following ischemia.