Transthyretin Promotes Axon Growth via Regulation of Microtubule Dynamics and Tubulin Acetylation

Transthyretin (TTR), a plasma and cerebrospinal fluid protein, increases axon growth and organelle transport in sensory neurons. While neurons extend their axons, the microtubule (MT) cytoskeleton is crucial for the segregation of functional compartments and axonal outgrowth. Herein, we investigated whether TTR promotes axon elongation by modulating MT dynamics. We found that TTR KO mice have an intrinsic increase in dynamic MTs and reduced levels of acetylated α-tubulin in peripheral axons. In addition, they failed to modulate MT dynamics in response to sciatic nerve injury, leading to decreased regenerative capacity. Importantly, restoring acetylated α-tubulin levels of TTR KO dorsal root ganglia (DRG) neurons using an HDAC6 inhibitor is sufficient to completely revert defective MT dynamics and neurite outgrowth. In summary, our results reveal a new role for TTR in the modulation of MT dynamics by regulating α-tubulin acetylation via modulation of the acetylase ATAT1, and suggest that this activity underlies TTR neuritogenic function.

Drug Related Problems and Complications of Bacterial Meningitis Admitted to Pediatrics Ward in Developing Country

Background: Bacterial meningitis is considered a medical emergency and it is a life-threatening infection that requires immediate treatment. However, even with an early diagnostic approach and adequate treatment with effective antibiotics, death and different complications may occur.Objective: This study aimed to assess drug related problems and its association on bacterial meningitis related complication.Method: A prospective hospital-based observational study was conducted at the pediatric ward of Hiwot Fana Specialized teaching hospital, Harar. This study was conducted longitudinally for consecutive one year from December 30/2019-Juanuary 1/2021 admitted to pediatrics ward. All pediatrics admitted with the diagnosis of bacterial meningitis and fulfilled the inclusion criteria. To identify independent predictors of bacterial meningitis related complication, binary logistic regression model were used using STATA, version 14.2. Stastical significance was declared at p<0.05Result: After 1 year follow up, 384 children were included in this study with a response rate of 98.1%. Males(55.73%) outnumbered. The mean age and cerebrospinal fluid protein were 5.01±0.19 and 60.5±4.53 respectively. Nearly half of the child had co-morbidity in addition to admission diagnosis, meningitis. Two hundred twenty four(58.33%) patients exposed to at least one type of drug related problem. One hundred twenty one (31.51%) children were developed bacterial meningitis related complications. Drug related problem(AOR=6.26, 95%CI: 3.58-10.93), cerebrospinal fluid protein(AOR=9.38, 95%CI: 9.81.9-96), age(AOR=0.01, 95%CI: 0.13-0.19), duration of illness(AOR=) and co-morbidity(AOR=13.18, 95%CI: 1.81-5.6) were absolutely associated with the occurrence of complication. Conclusion: Drug related problem and associated complications were substantial among children admitted with meningitis. This study identified significant association between drug related problem and complication. Health professional shall prevent drug related problem to prevent associated complication.

Anti-MOG autoantibody–associated schizophreniform psychosis

Objective: Autoimmune mechanisms are related to disease development in a subgroup of patients with psychosis. The contribution of immunoglobulin G (IgG) antibodies against myelin oligodendrocyte glycoprotein (MOG) is mainly unclear in this context. Methods: Therefore, two patients with psychosis and anti-MOG antibodies—detected in fixed cell-based and live cell-based assays—are presented. Results: Patient 1 suffered from late-onset psychosis with singular white matter lesions in MRI and intermittent EEG slowing. Patient 2 suffered from a chronic paranoid-hallucinatory disorder with intermittent confusional states, non-specific white matter alterations on MRI, a disorganized alpha rhythm on EEG and elevated cerebrospinal-fluid protein. Both patients had anti-MOG antibody titers of 1:320 in serum (reference<1:20). Conclusion: The arguments for and against a causal role for anti-MOG antibodies are discussed. The antibodies could be relevant, but due to moderate titers, they may have caused a rather “subtle clinical picture” consisting of psychosis instead of “classical” MOG encephalomyelitis.

Unique Cerebrospinal Fluid Profiles of Patients With Human Immunodeficiency Virus- Associated Cryptococcal Meningitis With a Ventriculoperitoneal Shunt : A Retrospective Cohort Study

Background: The long-term complications of ventriculoperitoneal shunting in patients with human immunodeficiency virus-associated cryptococcal meningitis remain unclear. We conducted a case-control study investigating the long-term effects of ventriculoperitoneal shunting in patients with human immunodeficiency virus-associated cryptococcal meningitis. Methods: Between January 2011 and December 2019, 112 patients with human immunodeficiency virus-associated cryptococcal meningitis from our hospital were enrolled in this retrospective cohort study. Of those, 30 (26.8%) patients underwent ventriculoperitoneal shunting (VPS group); the remaining (n = 82; 73.2%) were included in the non-VPS group. Survival was estimated using the Kaplan–Meier method. Univariate and multivariate Cox regression analyses were performed to identify factors associated with ventriculoperitoneal shunting. Results: The VPS group (n=21) had lower cerebrospinal fluid glucose (2.51±0.81 vs. 3.16±0.48 mmol/L; P=0.002) and higher cerebrospinal fluid protein levels (1.37 [0.83–1.49] vs. 0.49 [0.49–0.49] g/L; P=0.011) than did the non-VPS group (n=21). Intracranial pressure decreased from 400 (375–450) to 164 (145–172) mmH2O in the VPS group (log-rank, P<0.001). The 24-week cumulative survival rates in the VPS and non-VPS groups were 100.0% and 79.8%, respectively (P=0.035). The misdiagnosis rates of tuberculous meningitis were 28.6% and 0.0%, respectively (P=0.008). Conclusions: Ventriculoperitoneal shunting decreased the intracranial pressure and 24-week mortality in patients with human immunodeficiency virus-associated cryptococcal meningitis, but significantly increased cerebrospinal fluid protein levels, leading to a higher misdiagnosis rate of tuberculous meningitis. Physicians should be aware of these changes in the cerebrospinal fluid profiles of patients with human immunodeficiency virus-associated cryptococcal meningitis with a ventriculoperitoneal shunt.

Cerebrospinal Fluid Protein Concentration in Healthy Older Japanese Volunteers

The concentration of cerebrospinal fluid total protein (CSF-TP) is important for the diagnosis of neurological emergencies. Recently, some Western studies have shown that the current upper reference limit of CSF-TP is quite low for older patients. However, little is reported about the concentration of CSF-TP in the older Asian population. In this study, we retrospectively analyzed the CSF-TP concentrations in healthy older Japanese volunteers. CSF samples in 69 healthy Japanese volunteers (age range: 55–73 years) were collected by lumbar puncture, and the data of CSF were retrospectively analyzed. The mean (standard deviation) CSF-TP was 41.7 (12.3) mg/dL. The older group (≥65 years old) had higher CSF-TP concentration than the younger group (55–64 years old). The 2.5th percentile and 97.5th percentile of CSF-TP were estimated as 22.5 and 73.2 mg/dL, respectively, which were higher than the current reference range in Japan (10–40 mg/dL). Conclusions: The reference interval of CSF-TP in the older population should be reconsidered for the precise diagnosis of neurological emergencies.

Cerebrospinal Fluid Protein Concentration in Japanese Healthy Older Volunteers

The concentration of cerebrospinal fluid total protein (CSF-TP) is important for the diagnosis of neurological emergencies. Recently, some Western studies have shown that the current upper reference limit of CSF-TP is quite low for older patients. However, little is reported about the concentration of CSF-TP in older Asian population. In this study, we retrospectively analyzed the CSF-TP concentrations in Japanese healthy older volunteers. CSF samples in 69 healthy Japanese volunteers (age range: 55–73 years) were collected by lumbar puncture, and the data of CSF were retrospectively analyzed. The mean (standard deviation) CSF-TP was 41.7 (12.3) mg/dL. The older group (≥ 65 years old) had higher CSF-TP concentration than the younger group (55–64 years old). The 2.5th percentile and 97.5th percentile of CSF-TP were estimated as 22.5 and 73.2 mg/dL, respectively, which were higher than the current reference range in Japan (10–40 mg/dL).

Transthyretin promotes axon growth via regulation of microtubule dynamics and tubulin acetylation

Transthyretin (TTR), a plasma and cerebrospinal fluid protein, increases axon growth and organelle transport in sensory neurons. These TTR functions were suggested to underlie its activity in promoting nerve regeneration. While neurons extend their axons, the microtubule (MT) cytoskeleton is crucial for the segregation of functional compartments and axonal outgrowth. Herein, we investigated the hypothesis that TTR promotes axon elongation and regeneration by modulating MT dynamics. Indeed, we found that TTR KO mice have an intrinsic increase in dynamic MTs and reduced levels of acetylated α-tubulin in uninjured peripheral axons, and fail to modulate microtubule dynamics in response to sciatic nerve injury. Importantly, restoring acetylated α-tubulin levels of TTR KO DRG neurons using an HDAC6 inhibitor was sufficient to completely revert defective MT dynamics and neurite outgrowth. In summary, our results revealed a new role for TTR in the modulation of MT dynamics by regulating α-tubulin acetylation and support that this activity underlies TTR neuritogenic function.