Microglial depletion after brain injury prolongs inflammation and impairs brain repair, adult neurogenesis and pro-regenerative signaling.

The adult zebrafish brain, unlike mammals, has a remarkable regenerative capacity. Although inflammation in part hinders regeneration in mammals, it is necessary for zebrafish brain repair. Microglia are resident brain immune cells that regulate the inflammatory response. To explore the microglial role in repair, we used liposomal clodronate or colony stimulating factor-1 receptor (csf1r) inhibitor to suppress microglia after brain injury, and also examined regeneration in two genetic mutant lines that lack microglia. We found that microglial ablation impaired telencephalic regeneration after injury. Microglial suppression attenuated cell proliferation at the intermediate progenitor cell amplification stage of neurogenesis. Notably, the loss of microglia impaired phospho-Stat3 (signal transducer and activator of transcription 3) and ß-Catenin signaling after injury. Furthermore, the ectopic activation of Stat3 and ß-Catenin rescued neurogenesis defects caused by microglial loss. Microglial suppression also prolonged the post-injury inflammatory phase characterized by neutrophil accumulation, likely hindering the resolution of inflammation. These findings reveal specific roles of microglia and inflammatory signaling during zebrafish telencephalic regeneration that should advance strategies to improve mammalian brain repair.

A low-dose rituximab regimen for first-line treatment of acquired haemophilia A.

A low-dose rituximab regimen for first-line treatment of acquired haemophilia A. INTRODUCTION: Acquired haemophilia A (AHA) is a rare disease caused by the development of autoantibodies against FVIII. Diagnosis involves confirmation of FVIII deficiency and the presence of an inhibitor via the Bethesda assay. Severe bleeding is often managed with bypassing agents such as recombinant factor VII. This is then followed by eradication of the inhibitor with immunosuppression which typically includes a corticosteroid backbone. AIM: Review the current management and outcomes of AHA in Queensland, Australia. Determine the incidence, demographics and clinical characteristics of AHA patients. METHODS: Retrospective case series of AHA diagnosed between May 2014 and August 2018. Data were derived from the Australian Bleeding Disorders Registry and state-wide pathology database. Data collection proforma was completed by the treating haematologist and reviewed/compiled centrally. RESULTS: 24 patients were identified (incidence 1 in 1.27 million). The median age was 76.5 years. Median follow-up was 20 months. Index bleed was atraumatic and skin/soft tissue in the majority of patients. Recombinant FVIIa was the most commonly used haemostatic therapy and effective in 85% of patients. Immunosuppression and steroid usage were uniform. Upfront second agent was used in 75% of patients and was most commonly rituximab. 87.5% of patients achieved a complete remission in a median time of 48 days. Low-dose rituximab was frequently used and equally as efficacious as standard dose. CONCLUSION: Immunosuppression with combination therapy, notably rituximab, appears to be non-inferior and has a favourable side effect profile.

Declining Chlamydia and Gonorrhea Diagnoses Among Pregnant Women in South Carolina, 2008 to 2018.

BACKGROUND: Reported US cases of chlamydia and gonorrhea have increased since 2000, whereas studies in select populations suggest that the prevalence of these diseases has decreased. We sought to determine if these diagnoses are increasing among pregnant women delivering at our center. METHODS: This is a retrospective study of women delivering at least 1 infant >18 weeks of gestation at the Medical University of South Carolina for 11 years (2008-2018). Using the perinatal information system, we collected maternal race, age, insurer, and chlamydia and gonorrhea screening results during the pregnancy of record. Cochran-Armitage trend analyses were performed to evaluate trends in these diagnoses by delivery year for all women and for age/race subgroups. RESULTS: During the study period, there were 24,807 deliveries. The median age of women was 28 years (interquartile range, 23-32 years). Five percent (5.0%) of women were diagnosed with chlamydia and 1.2% with gonorrhea. The percent of women diagnosed decreased for both chlamydia (9.6%-3.4%) and gonorrhea (2.5%-1.1%; P < 0.001, trend analyses for both). A higher percentage of Black women had chlamydia and gonorrhea, and both diagnoses declined over time: 17.4% to 6.9% (P < 0.0001) for chlamydia and 5.8% to 2.1% (P < 0.0001) for gonorrhea. In a subanalysis of race and age, Black women younger than 25 years experienced the most significant decline in chlamydia diagnoses (P < 0.0001). CONCLUSIONS: We observed declining diagnoses of chlamydia and gonorrhea among pregnant women in our center. Although Black women delivering were more likely to have either diagnoses, they experienced a significant decline in both chlamydia and gonorrhea over time.

Sudden unilateral audiovestibular loss due to acute labyrinthine haemorrhage can be missed on early MRI brain sequences: case report.

Background: Labyrinthine haemorrhage is a rare vascular disorder often presenting with the triad of acute vertigo, sudden sensorineural hearing loss and tinnitus. There are minimal reports on imaging progression over the acute period. Index case: A woman in her mid-40s presented with acute vertigo, sudden left-sided hearing loss and tinnitus, consistent with acute unilateral audiovestibular loss. Left peripheral vestibular hypofunction was confirmed acutely on video head impulse testing, and pure tone audiometry showed a profound left sensorineural hearing loss. An MRI brain including diffusion-weighted imaging within 24 hours was normal. Delayed MRI brain and internal acoustic canal after 7 days demonstrated increased 3D fluid-attenuated inversion recovery and T1 signal throughout the left cochlea and semicircular canals, without contrast enhancement. This was consistent with labyrinthine haemorrhage. She received early oral prednisone followed by three doses of intratympanic dexamethasone. At 12 months follow-up the patient remained profoundly deaf, however, balance and vestibular symptoms improved with early vestibular physical rehabilitation. Conclusion: We report a case of acute labyrinthine haemorrhage missed on an early MRI brain sequence. This diagnosis should be considered in presentations of acute audiovestibular loss, and delayed MRI including internal auditory canal sequences may be important for diagnosis.

Real world molecular characterisation and clonal evolution of acute myeloid leukaemia reveals therapeutic opportunities and challenges.

Acute myeloid leukaemia (AML) is an aggressive haematological malignancy with poor prognosis. Increasing understanding of the molecular mechanisms driving clonal proliferation has resulted in advancements in classification and available therapeutic targets. Fms-related tyrosine kinase 3 (FLT3) mutations are prognostically important and offer options for targeted inhibition, however they are not stable and can emerge or disappear at relapse. Our aim was to review diagnostic testing of consecutive cases of newly diagnosed and relapsed AML reported across Queensland in comparison to available literature. We conducted a retrospective review of 1531 samples from 1231 patients to identify patterns of molecular testing and AML subtypes in our cohort. Outcomes included World Health Organization (WHO) classification, European LeukaemiaNet (ELN) risk category and rates of missed FLT3 mutation testing. Patients aged <60 years had significantly more favourable risk AML (48% vs 25%, p<0.01), with favourable risk chromosomal translocations [t(8;21) and inv(16)] being more common. Thirteen patients (1%) did not have FLT3 mutation testing at diagnosis, with 103 relapse samples (39%) not being tested. Eighteen patients (10%) had FLT3 mutations lost at relapse, with five patients (3%) developing new FLT3 mutations at relapse. This study identifies the subtypes and risk stratification of a large cohort of AML patients over an extended period. The relatively high rate of absent FLT3 mutation testing at relapse as well as FLT3 loss or gain highlights the potential missed opportunities for salvage treatment strategies.

Syndrome of inappropriate antidiuretic hormone secretion induced by a single dose of oral cyclophosphamide.

OBJECTIVE: To report a case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) induced by a single oral dose of cyclophosphamide. CASE SUMMARY: A 69-year-old woman was treated with oral CTD (cyclophosphamide/thalidomide/dexamethasone) chemotherapy for multiple myeloma. Two days after the first dose (including cyclophosphamide 500 mg), the patient developed vomiting, drowsiness, and headache. Medication history included sertraline, started in 2005. On admission, laboratory values were serum sodium 113 mEq/L, serum osmolality 240 mOsm/kg, urinary osmolality 701 mOsm/kg, urinary sodium 91 mEq/L, and serum creatinine 0.71 mg/dL. Thyroid and adrenal function were normal. SIADH was diagnosed. Cyclophosphamide and sertraline were stopped and fluid restriction was commenced. The patient was discharged on day 9 following chemotherapy with serum sodium 132 mEq/L. Sertraline was restarted. Four days later she developed vomiting with serum sodium 119 mEq/L. Fluid restriction, which the woman had not performed, was reinstituted and she was discharged on day 17. Two further cycles of chemotherapy were subsequently given without cyclophosphamide and serum sodium remained within normal limits. DISCUSSION: Cyclophosphamide-induced severe hyponatremia and SIADH have been documented in patients receiving treatment for a wide range of malignant and autoimmune disorders. All cases have involved intravenous therapy, with doses ranging from single pulse doses of 500 mg to 3000 mg/m(2). Selective serotonin reuptake inhibitors are a common cause of SIADH. Because sertraline was instituted in 2005 and reinstituted without incident, it was eliminated as a contributing factor. Malignancy, tumor lysis syndrome, other medications, hydration to prevent hemorrhagic cystitis, and renal impairment were also ruled out. The Naranjo probability scale indicated a probable association between SIADH and cyclophosphamide administration. CONCLUSIONS: To our knowledge, our report represents the first case of SIADH due to a single oral dose of cyclophosphamide. Clinicians should be aware of this rare adverse event, as it can have life-threatening consequences.

Educational Case: Bladder Urothelial Cell Carcinoma TNM Stage, Prognosis and Management.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. 1.

Cancer treatment in the extreme elderly: case study of a 100-year-old lymphoma patient.

Limited data are available on the treatment of older adults with cancer. Comorbidities may preclude the administration of effective therapies, particularly in the extreme elderly. Comprehensive geriatric assessment can identify specific weaknesses of the patient and predict unexpected toxicities, thus enabling an optimized treatment strategy in this population. We report a case of the successful management of a 99-year-old female lymphoma patient with a strong wish for active treatment to improve quality of life and prolong survival past her 100th birthday. This case demonstrates that cancer treatment in the extreme elderly is possible and highlights the need for a formalized treatment plan based on geriatric assessment, frank discussion with patients and families, and defined goals of therapy.