Heavy chain (AH) amyloidosis is a rare subtype of immunoglobulin-derived amyloidosis, comprising less than 1% of all systemic cases. While kidney involvement is frequently observed in systemic amyloidosis, presentations dominated by acute kidney injury (AKI) with glomerular bleeding and interstitial hemorrhage are uncommon. We report the case of a Japanese man in his 50s who developed AKI requiring dialysis. He had a history of proteinuria noted during previous health checkups but no known underlying diseases. Renal biopsy revealed amorphous mesangial and capillary wall deposits with weak periodic acid-Schiff and negative periodic acid-methenamine silver staining, and positivity for Congo red and direct fast scarlet. Electron microscopy showed non-branching fibrils, and laser microdissection followed by liquid chromatography-tandem mass spectrometry confirmed a diagnosis of AH amyloidosis. Of note, the biopsy also revealed numerous intratubular red blood cells and patchy interstitial hemorrhage in the absence of crescents or necrotizing lesions. The patient was initially treated with corticosteroids under the presumption of rapidly progressive glomerulonephritis. After histologic diagnosis, clone-directed daratumumab-based chemotherapy was introduced. Renal function gradually recovered, and dialysis was discontinued within 3 weeks of admission. This case highlights a rare but important phenotype of AH amyloidosis characterized by disruption of the glomerular capillaries and interstitial hemorrhage leading to reversible AKI. Early biopsy and appropriate therapeutic intervention may allow renal function to recover, even in severe presentations.
Gait disturbance in individuals with spinal cord injury (SCI) at levels rostral to the lumbar locomotor centre results from disconnection between the supraspinal system and the spinal locomotor centre. Here, we present a non-invasive volition-controlled spinal stimulation paradigm that empowers paraplegic individuals to regain stepping control in their impaired legs. Using hand muscle-controlled magnetic stimulation targeting the lumbar spinal motor circuits in the preserved lumber cord, individuals with chronic SCI achieved control of start-stop motion, step length and cadence of bilateral cyclic stepping in paralysed legs. Stimulus-induced cyclic stepping with leg muscle EMG activity was evoked in all participants with complete or incomplete SCI, regardless of the lesion site between the thoracic and lumbar spinal cord. Combining voluntary gait effort with closed-loop stimulation further enhanced leg movements. Repeated application of this closed-loop stimulation led to progressive improvement in stimulus-induced stepping and muscle responses, particularly in participants with thoracic SCI, and in stimulus-free stepping, particularly in participants with incomplete SCI. Our findings indicate that the preserved lumbar spinal motor circuit plays a crucial role in improving stimulus-induced stepping, whereas the preserved descending pathway is required for improving stimulus-free stepping. This non-invasive closed-loop spinal stimulation paradigm bypasses the lesion site on the spinal cord and strengthens both the preserved spinal circuits and the descending pathways to allow bilateral stepping control to be regained after SCI. This approach holds great promise for SCI-related gait rehabilitation because it has the potential to lead to functional recovery. Furthermore, this approach offers a viable alternative for individuals with contraindications to invasive procedures or those who do not consent to surgical treatments.
For a long time, from the nineteenth century to most of the twentieth century, the cerebellum was thought to be an organ that regulates movement. Towards the end of the twentieth century, the brain functions associated with the cerebellum began to extend beyond motor control. Now, there is a consensus that the cerebellum is involved not only in motor functions but also in the most basic autonomic functions and the most complex cognitive and emotional functions, with a focus on predictions and internal models. A new functional model of the cerebellum is needed to explain all layers of brain functions by extending predictive computations in the cerebellum. On the other hand, the cerebellum and the basal ganglia were believed to be independent and complementary motor centers that lacked direct neural connections. For example, in neurophysiology classes in the 1980s, the characteristics of cerebellar ataxia were summarized as hyperkinetic and hypotonia, while the characteristics of Parkinson's disease (traditionally classified as "basal ganglia disorder") were summarized as hypokinetic and hypertonia, and therefore their functions were assumed at opposite poles, without interactions between the two main subcortical systems. The cerebellum and the basal ganglia were also assigned contrasting models regarding their learning mechanisms. Namely, the cerebellum was assumed to employ supervised learning with error signals, while the basal ganglia were assumed to employ reinforcement learning with reward prediction errors. However, recent neuroanatomical studies have demonstrated a number of novel connections between them, questioning their independence. Moreover, recent single-neuron recording and inactivation studies provided evidence that the cerebellum may also be involved in reinforcement learning. The cerebellum is neither independent of the basal ganglia nor exclusively specialized for supervised learning. We now need a new, general model to explain the contradiction between the known uniformity of the cerebellar cortex's structure and the newly added diversity of brain functions to which the cerebellum contributes. This consensus paper summarizes many of the seeds of such a new theory. The panel of experts (1) highlights the importance of the anatomical connectivity between cerebellar circuitry and basal ganglia, (2) points out that the anatomy of the cerebellum is unique and allows predictive computations in motor and extra-motor domains such as cognition, affect, social interactions and reward processes, (3) underlines the need to further elucidate the nature of interactions between cerebellar cortex and cerebellar nuclei to better understand cerebellar and psychiatric disorders and (4) suggests that common operations may underlie the motor and non-motor functions of the cerebellar circuitry. Cerebellar models remain a major topic of research to improve our understanding of the numerous cerebellar activities and to better understand the complexity of cerebellar disorders.
TDP-43 proteinopathies, such as frontotemporal degeneration (FTLD) and amyotrophic lateral sclerosis (ALS), are classified into five neuropathological subtypes, Types A to E, according to the morphology of TDP-43 inclusions. Recent cryo-electron microscopy analysis of FTLD-TDP cases demonstrated that TDP-43 filaments composing the inclusions are structurally different depending on the subtype, and remarkably, co-assembled heteromeric filaments of TDP-43 and annexin A11 (ANXA11) were identified in Type C. Therefore, the involvement of ANXA11 in TDP-43 proteinopathy should be further examined. Here, we pathologically and biochemically analyzed four cases of primary lateral sclerosis-phenotype FTLD/motor neuron disease (MND) with TDP-43 pathology (PLS-TDP), and found that ANXA11 co-localizes with FTLD-TDP Type A pathology in PLS-TDP. Immunoblot analysis of the PLS-TDP cases revealed that the banding patterns of C-terminal and chymotrypsin-resistant fragments of TDP-43 are distinct from those of FTLD-TDP Types A, B and C. In addition, the N-terminal fragments of ANXA11 appear to be different from those of FTLD-TDP Type C. Filaments extracted from PLS-TDP cases were TDP-43- and ANXA11-immunopositive, suggesting the presence of TDP-ANXA11 heteromeric filaments. These results suggest that co-aggregation of ANXA11 and TDP-43 may serve as a neuropathological and biochemical indicator distinguishing PLS from ALS in FTLD/MND.
Pycnogenol (PYC), a standardized extract derived from the bark of the French maritime pine (Pinus pinaster ssp. atlantica), exhibits a broad spectrum of biological activities, including antioxidant, anti-inflammatory, immunomodulatory, antiviral, and anticancer effects. These effects are attributed to the rich profile of polyphenolic compounds, which confer potent antioxidant and anti-inflammatory properties. Viral infections frequently induce oxidative stress, inflammation, and immune dysregulation, thereby posing substantial challenges to global public health. Accordingly, the development of effective antiviral agents applicable across diverse viral outbreak settings remains a critical goal. PYC has demonstrated antioxidant, anti-inflammatory, and antiviral potential against several viruses, including hepatitis C virus, dengue virus, and severe acute respiratory syndrome coronavirus 2. In addition, PYC exhibited anticancer activity by modulating cell signaling pathways, inhibiting tumor cell proliferation, inducing apoptosis, and suppressing angiogenesis. However, further research and clinical validation are required to confirm its therapeutic applications. Accordingly, this review summarizes the current understanding regarding the antioxidant, anti-inflammatory, and anticancer mechanisms of PYC. Moreover, the review highlights its immunomodulatory properties to inform future antiviral and anticancer drug development and therapeutic strategies.
