Thyroid hormone (TH) is required for normal development as well as regulating metabolism in the adult. The thyroid hormone receptor (TR) isoforms, α and β, are differentially expressed in tissues and have distinct roles in TH signaling. Local activation of thyroxine (T4), to the active form, triiodothyronine (T3), by 5′-deiodinase type 2 (D2) is a key mechanism of TH regulation of metabolism. D2 is expressed in the hypothalamus, white fat, brown adipose tissue (BAT), and skeletal muscle and is required for adaptive thermogenesis. The thyroid gland is regulated by thyrotropin releasing hormone (TRH) and thyroid stimulating hormone (TSH). In addition to TRH/TSH regulation by TH feedback, there is central modulation by nutritional signals, such as leptin, as well as peptides regulating appetite. The nutrient status of the cell provides feedback on TH signaling pathways through epigentic modification of histones. Integration of TH signaling with the adrenergic nervous system occurs peripherally, in liver, white fat, and BAT, but also centrally, in the hypothalamus. TR regulates cholesterol and carbohydrate metabolism through direct actions on gene expression as well as cross-talk with other nuclear receptors, including peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), and bile acid signaling pathways. TH modulates hepatic insulin sensitivity, especially important for the suppression of hepatic gluconeogenesis. The role of TH in regulating metabolic pathways has led to several new therapeutic targets for metabolic disorders. Understanding the mechanisms and interactions of the various TH signaling pathways in metabolism will improve our likelihood of identifying effective and selective targets.

Thyroid Hormone Regulation of Metabolism

Research in Parkinson's disease (PD) genetics has been extremely prolific over the past decade. More than 13 loci and 9 genes have been identified, but their implication in PD is not always certain. Point mutations, duplications and triplications in the alpha-synuclein (SNCA) gene cause a rare dominant form of PD in familial and sporadic cases. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a more frequent cause of autosomal dominant PD, particularly in certain ethnic groups. Loss-of-function mutations in Parkin, PINK1, DJ-1 and ATP13A2 cause autosomal recessive parkinsonism with early-onset. Identification of other Mendelian forms of PD will be a main challenge for the next decade. In addition, susceptibility variants that contribute to PD have been identified in several populations, such as polymorphisms in the SNCA, LRRK2 genes and heterozygous mutations in the beta-glucocerebrosidase (GBA) gene. Genome-wide associations and re-sequencing projects, together with gene-environment interaction studies, are expected to further define the causal role of genetic determinants in the pathogenesis of PD, and improve prevention and treatment.

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Parkinson's disease: from monogenic forms to genetic susceptibility factors

Neurotoxic side effects of cancer therapy are second in frequency to hematological toxicity. Unlike hematological side effects that can be treated with hematopoietic growth factors, neuropathies cannot be treated and protective treatment strategies have not been effective. For the neurologist, the diagnosis of a toxic neuropathy is primarily based on the case history, the clinical and electrophysiological findings, and knowledge of the pattern of neuropathy associated with specific agents. In most cases, toxic neuropathies are length-dependent, sensory, or sensorimotor neuropathies often associated with pain. The platinum compounds are unique in producing a sensory ganglionopathy. Neurotoxicity is usually dependent on cumulative dose. Severity of neuropathy increases with duration of treatment and progression stops once drug treatment is completed. The platinum compounds are an exception where sensory loss may progress for several months after cessation of treatment ("coasting"). As more effective multiple drug combinations are used, patients will be treated with several neurotoxic drugs. Synergistic neurotoxicity has not been extensively investigated. Pre-existent neuropathy may influence the development of a toxic neuropathy. Underlying inherited or inflammatory neuropathies may predispose patients to developing very severe toxic neuropathies. Other factors such as focal radiotherapy or intrathecal administration may enhance neurotoxicity. The neurologist managing the cancer patient who develops neuropathy must answer a series of important questions as follows: (1) Are the symptoms due to peripheral neuropathy? (2) Is the neuropathy due to the underlying disease or the treatment? (3) Should treatment be modified or stopped because of the neuropathy? (4) What is the best supportive care in terms of pain management or physical therapy for each patient? Prevention of toxic neuropathies is most important. In patients with neuropathy, restorative approaches have not been well established. Symptomatic and other management are necessary to maintain and improve quality of life.

Chemotherapy-induced neuropathy.

https://www.medtrition.com/wp-content/uploads/2014/09/Chemotheraphy-induced_peripheral_neuropathy-Prevention_and_treatment_strategies.pdf

Chemotherapy-induced peripheral neuropathy: Prevention and treatment strategies

Microtubule-stabilizing agents (MTSAs), including the taxanes and epothilones, are effective chemotherapeutic agents for the treatment of many cancers. Neuropathy is a major adverse effect of MTSA-based chemotherapy, with severe peripheral neuropathy (grade 3 or 4) occurring in as many as 30% of patients treated with a MTSA. MTSA-induced neuropathy usually resolves gradually after cessation of the treatment. The most reliable method to accurately assess MTSA-induced neuropathy is by clinical evaluation, although additional techniques are being developed and evaluated. Among MTSA-induced neuropathy, the most extensively studied is that induced by taxanes; such a neuropathy usually presents as sensory neuropathy and is more common with paclitaxel than docetaxel. The incidence of MTSA-induced neuropathy seems to depend on the MTSA dose per treatment cycle, the schedule of treatment, and the duration of the infusion. Although there have been several small clinical trials with neuroprotective agents, early recognition and supportive care are the best approaches for prevention and management of MTSA-induced neuropathy. In the future, research should focus on elucidating the mechanism of MTSA-induced neuropathy, developing reliable in vivo and in vitro preclinical models to study MTSA-induced neuropathy, developing a more reliable grading system for MTSA-induced neuropathy, developing more reliable methods for evaluating MTSA-induced neuropathy, and evaluating the efficacy of potential neuroprotective agents in clinical trials.

Peripheral Neuropathy Induced by Microtubule-Stabilizing Agents

Vitamin E for prophylaxis against chemotherapy- induced neuropathy : A randomized controlled trial. Authors' reply

Context: Recently the first patients with inactivating mutations in T3 receptor (TR)-α1 have been identified. These patients have low free T4, low T4, high T3, low rT3, and normal TSH serum levels, in combination with growth retardation, delayed bone development, and constipation. Objective: The aim of the current study was to report the effects of levothyroxine (LT4) treatment on the clinical phenotype of 2 patients (father and daughter) with a heterozygous inactivating mutation in TRα1. Setting and Participants: Both patients were treated with LT4 for the last 5 years. To evaluate the effect of LT4 treatment, LT4 was withdrawn for 35 days and subsequently reinitiated. Data were collected from medical records, by reanalysis of serum collected over the last 6 years, and by a detailed clinical evaluation. Results: Treatment with LT4 resulted in a suppression of serum TSH and normalization of serum free T4 and rT3, whereas T3 levels remained elevated in both patients. In addition, there was a normalization ...

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Clinical phenotype of a new type of thyroid hormone resistance caused by a mutation of the TRα1 receptor: consequences of LT4 treatment

The authors sought to identify factors associated with poor compliance with driving restrictions due to a diagnosis of epilepsy. They compared the demographic and clinical characteristics of 60 patients with epilepsy who, despite the authors' recommendation, continued to drive, with those of 60 age- and sex-matched epileptic patients who refrained from driving. The results showed that patients with epilepsy do not comply with driving restrictions, mainly for employment-related reasons.

Factors associated with poor compliance of patients with epilepsy driving restrictions.

A 40-year-old HIV-negative Greek woman was admitted to the Department of Neurology at the University Medical Center of Patras with a 4-day history of progressive muscle weakness in her legs, accompanied by fever (39.5°C), diarrhea and urine retention and a 6-year history of oral and genital lesions that had relapsed 20 days prior to admission. Physical examination revealed multiple large aphthous lesions in the oral mucosa, extensive and deep anogenital ulcers, pseudofolliculitis and pathergy signs but no evidence of arthritis. Initial neurological examination showed muscle power grade 3/5 [Medical Research Council (MRC) scale] in the proximal and grade 4/5 in the distal muscles], brisk symmetrical tendon reflexes, extensor plantar response bilaterally, severe suppression of vibration sense below the knees (particularly on the right extremity) and bilateral reduction of pain appreciation below the T5 level. Neurological disability score in the expanded disability status scale (EDSS) was 6.5, indicating that bilateral assistance was required to walk 20 m. Cranial nerves and motor and sensory function of upper limbs were normal. Magnetic resonance imaging (MRI) of thoracic spinal cord revealed a long intramedullar lesion extending from C7 to T7 vertebrae with gadolinium-enhancement at T3–T4 level, whereas that of the brain showed three unenhanced small lesions at the brainstem (Figure 1.). Cerebrospinal fluid analysis revealed 60 lymphocytes/ml, normal protein and glucose content and negative oligoclonal bands. 



Figure 1. 
Magnetic resonance scan of the thoracic cord (sagittal T1-weighted images with gadolinium) showing the intramedullary enhanced lesion before (left image) and 1 month after treatment (right image).



Ophthalmologic investigation disclosed posterior uveitis and spotty hemorrhagic foci on both eyes, whereas colonoscopy showed multiple deep ulcers along the large bowel. Erythrocyte sedimentation rate was 70 mm/h, HLA B51 was positive, whereas serum protein electrophoresis revealed a decrease …

Interferon-α treatment for acute myelitis and intestinal involvement in severe Behçet’s disease

The current study aimed to assess the viability of sympathetic sudomotor fibers in cancer patients treated with cisplatin or paclitaxel-based chemotherapy and to ascertain whether this method could contribute to the diagnostic sensitivity of conventional techniques. Sympathetic skin response (SSR) from the hand and sole of 23 cancer patients (nine females and 14 males, mean age 62.4 +/- 10.5 years) was recorded unilaterally before and after chemotherapy with six courses of cumulative cisplatin or paclitaxel containing regimens. Clinical and electrophysiological data were also collected and correlated with the SSR results. Twenty-three healthy subjects served as controls. SSR abnormalities were only present in patients with evidence of peripheral neuropathy assessed by conventional nerve conduction techniques. Three patients had absent SSR in the upper limb whilst six patients had absent SSR both in the upper and lower limbs. In the upper limb, the mean SSR latency was not significantly altered through time (P = 0.086). In the lower limb the mean delay from baseline to follow-up was significantly changed (P = 0.029). In patients, the mean SSR latency was significantly prolonged compared with controls in both upper limb (P = 0.001) and lower limb (P = 0.000). SSR abnormalities were strongly related to sensory conduction abnormalities as detected by conventional techniques (r = 0.39, P = 0.004). Our results showed that SSR does not seem to add to the diagnostic sensitivity of conventional techniques in chemotherapy-induced neuropathy. However, its role in the disclosure of small fibers neuropathy abnormalities is worth considering. Further studies are warranted to address this important issue.

E. Chroni

Papers

Vitamin E for prophylaxis against chemotherapy- induced neuropathy : A randomized controlled trial. Authors' reply

Clinical phenotype of a new type of thyroid hormone resistance caused by a mutation of the TRα1 receptor: consequences of LT4 treatment

Factors associated with poor compliance of patients with epilepsy driving restrictions.

Interferon-α treatment for acute myelitis and intestinal involvement in severe Behçet’s disease

The impact of paclitaxel or cisplatin-based chemotherapy on sympathetic skin response : a prospective study