RESUMEN
Diabetes mellitus renders both widespread and localized irreversible damage to peripheral axons while imposing critical limitations on their ability to regenerate. A major failure of regenerative capacity thereby imposes a 'double hit' in diabetic patients who frequently develop focal neuropathies such as carpal tunnel syndrome in addition to generalized diffuse polyneuropathy. The mechanisms of diabetic neuron regenerative failure have been speculative and few approaches have offered therapeutic opportunities. In this work we identify an unexpected but major role for PTEN upregulation in diabetic peripheral neurons in attenuating axon regrowth. In chronic diabetic neuropathy models in mice, we identified significant PTEN upregulation in peripheral sensory neurons of messenger RNA and protein compared to littermate controls. In vitro, sensory neurons from these mice responded to PTEN knockdown with substantial rises in neurite outgrowth and branching. To test regenerative plasticity in a chronic diabetic model with established neuropathy, we superimposed an additional focal sciatic nerve crush injury and assessed morphological, electrophysiological and behavioural recovery. Knockdown of PTEN in dorsal root ganglia ipsilateral to the side of injury was achieved using a unique form of non-viral short interfering RNA delivery to the ipsilateral nerve injury site and paw. In comparison with scrambled sequence control short interfering RNA, PTEN short interfering RNA improved several facets of regeneration: recovery of compound muscle action potentials, reflecting numbers of reconnected motor axons to endplates, conduction velocities of both motor and sensory axons, reflecting their maturation during regrowth, numbers and calibre of regenerating myelinated axons distal to the injury site, reinnervation of the skin by unmyelinated epidermal axons and recovery of mechanical sensation. Collectively, these findings identify a novel therapeutic approach, potentially applicable to other neurological conditions requiring specific forms of molecular knockdown, and also identify a unique target, PTEN, to treat diabetic neuroregenerative failure.
Asunto(s)
Axones/metabolismo , Neuropatías Diabéticas/metabolismo , Regeneración Nerviosa/fisiología , Fosfohidrolasa PTEN/metabolismo , Animales , Western Blotting , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatología , Neuropatías Diabéticas/fisiopatología , Técnicas de Silenciamiento del Gen , Inmunohistoquímica , Masculino , Ratones , Compresión Nerviosa , Fosfohidrolasa PTEN/genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Patients admitted to intensive care units (ICUs) suffer from a wide range of neurological disorders. Some develop within the ICU rendering weakness and difficulty in weaning patients from ventilator support. ICUAW, or ICU acquired weakness, is a broad term that includes several more specific neuromuscular problems. After exclusion of other causes of weakness, ICUAW includes critical illness polyneuropathy (CIP), first described by Charles Bolton, critical illness myopathy (CIM), and disorders of neuromuscular junction transmission. This chapter reviews the clinical, electrophysiological, and pathological features of these conditions and provides clinicians with approaches toward diagnosing and investigating ICUAW.
Asunto(s)
Enfermedad Crítica , Enfermedades Neuromusculares/complicaciones , Enfermedades del Sistema Nervioso Periférico/complicaciones , Historia del Siglo XIX , Historia del Siglo XX , Humanos , Unidades de Cuidados Intensivos , Enfermedades Neuromusculares/clasificación , Enfermedades Neuromusculares/diagnóstico , Enfermedades Neuromusculares/historia , Enfermedades del Sistema Nervioso Periférico/diagnósticoAsunto(s)
Ventrículos Cerebrales/anomalías , Ventrículos Cerebrales/patología , Epilepsia Tónico-Clónica/diagnóstico , Imagen por Resonancia Magnética , Malformaciones del Desarrollo Cortical/diagnóstico , Heterotopia Nodular Periventricular/diagnóstico , Adulto , Epéndimo/anomalías , Epéndimo/patología , Femenino , Humanos , Aumento de la ImagenRESUMEN
We report three patients with ophthalmic herpes zoster (HZ) manifestations on the background diagnosis of multiple myeloma (MM). It seems that immunocompromised status has caused reactivation of the varicella zoster virus (VZV) producing a well-characterised neurological syndrome and subsequent postherpetic neuralgia in two patients. One patient experienced lymphocytic leptomeningitis resulting in unilateral optic neuritis. All patients received similar myeloma disease-specific treatment prior to HZ reactivation. All patients were treated with thalidomide and steroids, and they thereafter underwent autologous stem cell transplantation. Prior to HZ reactivation they received new immunomodulatory drugs in the form of thalidomide in addition to bortezomib (2 patients) and lenalidomide (1 patient). Immediate specific antiviral therapy was successfully applied with intravenous acyclovir for 10 days, followed by long-term oral famciclovir maintenance. Two patients progressed to have chronic HZ ophthalmicus and postherpetic neuralgia requiring ongoing antiviral therapy and neuroepileptic medications for the neuropathic pain.