Addressing the Unintentional Consequences of Cancer Therapy With Novel Integrative Therapeutics.

There are 15.5 million cancer survivors in the United States because of, in part, improvements in therapy. As a result, there will be an increased burden of long- and late-term complications of cancer care, such as metabolic alterations. These metabolic changes will include alterations in bone resorption, obesity, hypercholesterolemia, and diabetes mellitus. The majority of cancer treatment-related toxicities have focused on endocrine therapy; however, chemotherapy and supportive medications, such as steroids, contribute to the development of these disorders. Because of the chronicity of these metabolic changes and their impact on morbidity, cancer risk, and outcomes as well other negative effects, including musculoskeletal pain and vasomotor symptoms, alternative strategies must be developed. These strategies should include nonpharmacologic approaches. Here, we summarize metabolic changes secondary to cancer care and integrative approaches to help alleviate therapy-associated toxicities.

[Cerebral insulin resistance: current concepts of the pathogenesis and possible therapeutic strategies]. / Tserebral'naia insulinorezistentnost': sovremennye predstavleniia o patogeneze i vozmozhnye terapevticheskie strategii.

The review presents current concepts about the problem of cerebral insulin resistance (IR). It has now been established that cerebral IR plays a key role in the pathogenesis of degenerative and metabolic diseases of the brain. Based on literature data and own clinical experience, the authors recommend to use the standardized extract of ginkgo biloba EGb761 as a cellular protector, which increases insulin sensitivity of cells and reduces atherogenesis, in order to improve cognitive functions and quality of life in patients with diabetes mellitus.

Treatment Perspectives Based on Our Current Understanding of Concussion.

Sports-related concussion also referred to in the literature as mild traumatic brain injury remains a popular area of study for physicians, neurologists, neuropsychologists, neuroimaging, athletic trainers, and researchers across the other areas of brain sciences. Treatment for concussion is an emerging area of focus with investigators seeking to improve outcomes and protect patients from the deleterious short-term and long-term consequences which have been extensively studied and identified. Broadly, current treatment strategies for athletes recovering from concussion have remained largely unchanged since early 2000s. Knowledge of the complex pathophysiology surrounding injury should improve or advance our ability to identify processes which may serve as targets for therapeutic intervention. Clinicians working with athletes recovering from sports-related concussion should have an advanced understanding of the injury cascade and also be aware of the current efforts within the research to treat concussion. In addition, how clinicians use the word "treatment" should be carefully defined and promoted so the patient is aware of the level of intervention and what stage of recovery or healing is being affected by a specific intervention. The purpose of this review is to bring together efforts across disciplines of brain science into 1 platform where clinicians can assimilate this information before making best practices decisions regarding the treatment of patients and athletes under their care.

Clinical awareness for health care professionals: Fatal encephalopathy complicating persistent vomiting in pregnancy.

Women with persistent vomiting during pregnancy need early referral to appropriate health facilities. Delayed referral and inappropriate management may lead to metabolic encephalopathy from a variety of causes, including electrolyte derangements or thiamine deficiency (Wernicke's encephalopathy) (WE). We present a case of persistent vomiting in pregnancy in which there was delayed referral, inappropriate treatment and failure to associate neurological signs such as terminal neck stiffness with WE, resulting in poor fetomaternal outcomes. In this report, we discuss the following lessons: (i) the need for early transfer of a patient with persistent vomiting and enigmatic clinical features to a higher healthcare facility; (ii) failure to associate neurological signs with complications of hyperemesis gravidarum/WE; (iii) lack of thiamine supplementation; and (iv) the advantages of magnetic resonance imaging over a computed tomography scan in the diagnosis of WE.

Hypoglycemic and antioxidant activities of paeonol and its beneficial effect on diabetic encephalopathy in streptozotocin-induced diabetic rats.

Diabetic encephalopathy (DE) is one of the severe complications in patients with diabetes mellitus. Paeonol, an active compound isolated from the root bark of Paeonia suffruticosa, has significant antidiabetic activity in vivo. However, its underlying beneficial effects on DE were unclear. In the present study, the protective activity of paeonol on DE was evaluated in streptozotocin (STZ)-induced diabetic rats. Paeonol at 50 and 100 mg/kg significantly increased body weight and decreased blood glucose levels, glycosylated serum proteins, and serum advanced glycation end products (AGEs) levels. Immunohistochemistry assays and Western blot analysis revealed a significant decrease in expressions on receptor for advanced glycation end products (RAGE) and nuclear factor kappa B (NF-κB) in hippocampus and cerebral cortical neurons after paeonol treatment. Furthermore, paeonol significantly increased glutathione content and remarkedly decreased induced nitric oxide synthase activity in hippocampus tissue. Our findings indicated that paeonol could improve the pathological damage of DE in STZ-induced diabetic rats. It might be associated with the modulating AGEs/RAGE/NF-κB pathway. This study suggested that paeonol might be a promising candidate for the prevention and treatment of DE.

17ß-Estradiol and genistein acute treatments improve some cerebral cortex homeostasis aspects deteriorated by aging in female rats.

Aging is associated with decreased insulin sensitivity and impaired cerebral glucose homeostasis. These changes increase neural sensitivity to metabolic damage contributing to cognitive decline, being the decrease in plasma estrogen following menopause one of the main factors involved in aged females. Phytoestrogens as genistein are structurally similar to 17ß-estradiol, bind to estrogen receptors, and can evoke both estrogenic and anti-estrogenic effects. Estrogens and phytoestrogens have neuroprotective potential, but the physiological mechanisms are not fully understood. Young and aged female Wistar rats were ovariectomized and treated acutely with 17ß-estradiol (1.4µg/kg body weight), genistein (10 or 40 mg/kg body weight), or vehicle. Cortical expression of glucose transporter-3 (GLUT-3) and -4 (GLUT-4), cytochrome c oxidase (CO), estrogen receptor-α (ERα) and -ß (ERß) was measured by Western blotting. There was an age-related decline in GLUT-4, CO and ERß levels. Both drugs, estradiol and genistein, were able to reverse GLUT-3 downregulation in the cortex following late ovariectomy. However, genistein was the only treatment able to restore completely GLUT-4 levels in aged rats. In contrast, estradiol was more potent than genistein at increasing CO, a marker of cerebral oxidative metabolism. As regards ER levels, estradiol increased the ERα67 quantity diminished by late ovariectomy, while genistein did the same with the other ERα isoform, ERα46, highlighting drug-specific differences in expression changes for both isoforms. On the other hand, no treatment-related differences were found regarding ERß levels. Therefore, genistein like estradiol could be suitable treatments against cortical metabolic dysfunction caused by aging. These treatments may hold promise as neuroprotective strategies against diabetes and age-related neurodegenerative diseases.

Auditory system dysfunction due to infantile thiamine deficiency: long-term auditory sequelae.

Eleven infants who were fed a thiamine-deficient formula for a mean of 3 months were evaluated for immediate and long-term auditory abnormalities. At presentation, 8 infants had auditory neuropathy spectrum disorder (ANSD), which resolved with supplementary thiamine in 5 children, was permanent in 2 children, and deteriorated in 1 patient who died at the age of 7 years. An additional patient had an auditory pattern corresponding to that of auditory neuropathy of brain stem origin. The 2 remaining patients had unilateral cochlear hearing loss. Six to 8 years later, all patients with transient ANSD had normal audiograms, 2 patients had unilateral cochlear hearing loss, and the rest had neural hearing loss. All survivors had a language developmental delay and impaired speech intelligibility of varying degrees, especially in the presence of background noise. Thiamine is crucial for normal auditory development and function, and its deficiency may be considered an acquired metabolic cause of ANSD in infants.

[Wernicke's encephalopathy associated with pellagra encephalopathy: rare and unusual complication in an elderly woman hospitalized for aspiration pneumonia]. / Encéphalopathie de Gayet Wernicke associée à une encéphalopathie pellagrique : complication rare et inhabituelle chez une femme âgée hospitalisée pour pneumopathie d'inhalation.

INTRODUCTION: Wernicke's encephalopathy caused by thiamine deficiency is typically characterised by a mental-status change, oculomotor dysfunction and an ataxia. Pellagra is the clinical presentation of niacin deficiency comprising cutaneous, gastrointestinal and neuropsychiatric manifestations. OBSERVATION: We report a case of encephalopathy due to dual vitamin deficiency of both thiamine (vitamin B1) and niacin (vitamin PP) in an 80-year-old women, hospitalized for severe sepsis caused by aspiration pneumonia. Severe malnutrition and alcohol consumption pointed to a diagnosis of vitamin deficiency. The clinical presentation and magnetic resonance imaging (MRI) were compatible with Wernicke's encephalopathy that remained irreversible despite vitamin B1 supplementation. Niacin supplementation allowed for complete regression of the observed symptoms compatible with niacin deficiency. CONCLUSION: Malnourished and alcoholic patients showing signs of encephalopathy should receive supplemental multivitamins including niacin.

Suspected acquired hypocobalaminaemic encephalopathy in a cat: resolution of encephalopathic signs and MRI lesions subsequent to cobalamin supplementation.

UNLABELLED: PRESENTING SIGNS AND INITIAL INVESTIGATIONS: An 8-year-old female spayed British shorthair cat was presented with a history of waxing and waning neurological signs. Neuroanatomical localisation was consistent with a diffuse forebrain disease. Blood ammonia concentration was increased. Abdominal ultrasonography and a bile acid stimulation test were normal. Magnetic resonance imaging (MRI) revealed hyperintense, bilaterally symmetrical, diffuse lesions on T2-weighted sequences, predominantly, but not exclusively, affecting the grey matter. Serum cobalamin (vitamin B12) concentration was low. Hypocobalaminaemia resulting in a urea cycle abnormality was considered a likely cause of the hyperammonaemia. TREATMENT: Daily cobalamin injections resulted in a rapid clinical improvement. Eight weeks into treatment neurological examination was unremarkable and there was complete resolution of the MRI lesions. CLINICAL IMPORTANCE: This is the first reported case of acquired feline hypocobalaminaemia resulting in an encephalopathy. Additionally, this case is unique in describing reversible brain MRI abnormalities in a cobalamin-deficient companion animal.

A review on the metabolic disorders of iodine deficiency.

Iodine is in the crucial parts of two hormones of T4 and T3 produced by the thyroid glands which are essential for all the aspects of human metabolisms. It is demonstrated that iodine deficiency can be considered as sole cause of many thyroid abnormalities including mental disorders. Iodine deficiency of sufficient degree to cause hypothyroidism during fetus life and early infancy will be accompanied with brain abnormality possibly to the stage of mental retardation. The iodine deficiency among subjects in their early stage of childhood is not as severe as those in their fetus or infancy. In adult subjects the sever iodine deficiency can be also associated with mental disorders due to the direct side effects of hypothyroidism occurred by lack of iodine. The clinical manifestation of iodine deficiency show itself with psychological disorders in adult subjects. The status of iodine within blood can be evaluated through measurement of urinary iodine level and the low urinary concentration is an indicative of hypothyroidism. Mental retardation and brain damage due to iodine deficiency can be prevented if iodine supplementation prescribed duly on time.

Sunitinib-induced hyperammonemic encephalopathy in gastrointestinal stromal tumors.

OBJECTIVE: To report 2 cases of hyperammonemic encephalopathy induced by sunitinib in patients with metastatic gastrointestinal stromal tumor (GIST). CASE SUMMARY: A 58-year-old man with imatinib-resistant metastatic GIST presented to the emergency department with confusion that developed 17 days after the initiation of sunitinib 50 mg/day. His serum ammonia level was markedly elevated (210 µg/dL). Sunitinib was discontinued, and an enema with lactulose was administered every hour. His neurologic status normalized within 24 hours and his serum ammonia level decreased to 64 µg/dL. A 68-year-old woman with imatinib-resistant metastatic GIST was admitted into the emergency department with confusion and irritability that developed 10 days after the start of sunitinib therapy. Her serum ammonia level was markedly elevated (389 µg/dL). Sunitinib was discontinued, and an enema with lactulose was administered every hour. Within 24 hours, her mental status was improved and her serum ammonia level was decreased to 116 µg/dL. Sunitinib was reintroduced, and the same symptoms occurred after day 7 of administration. Sunitinib was not prescribed afterward and the woman did not experience any further encephalopathic symptoms. DISCUSSION: Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases such as stem cell factor receptor, vascular endothelial growth factor, and platelet-derived growth factor. It is used as second-line therapy for patients with imatinib-resistant GIST. Hyperammonemic encephalopathy is an uncommon fatal complication of chemotherapy. According to the Naranjo probability scale, sunitinib was a probable cause of hyperammonemic encephalopathy in the patients described here. Although the mechanism of hyperammonemia is unclear, hyperammonemic encephalopathy might be caused by a vascular disorder related to the antiangiogenic properties of sunitinib, and it has ethnic differences associated with genetic polymorphisms. CONCLUSIONS: Sunitinib may induce hyperammonemic encephalopathy in some patients. Although further studies are warranted, clinicians should be aware of this severe adverse event when using sunitinib for treatment of GIST.

1H-magnetic resonance spectroscopy indicates damage to cerebral white matter in the subacute phase after CO poisoning.

OBJECTIVE: The authors examined whether (1)H-magnetic resonance spectroscopy (MRS) can identify damage to the centrum semiovale in the subacute phase after CO exposure. METHODS: Subjects comprised 29 adult patients who were treated with hyperbaric oxygenation within a range of 4-95 h (mean 18.7 h) after CO exposure. Subjects were classified into three groups according to clinical behaviours: Group A, patients with transit acute symptoms only; Group P, patients with persistent neurological symptoms; and Group D, patients with 'delayed neuropsychiatric sequelae' occurring after a lucid interval. MRS of bilateral centrum semiovale was performed 2 weeks after CO inhalation for all patients and 13 healthy volunteers. The mean ratios of choline-containing compounds/creatine ((mean)Cho/Cr) and N-acetylaspartate/Cr ((mean)NAA/Cr) for bilateral centrum semiovale were calculated and compared between the three CO groups and controls. Myelin basic protein (MBP) concentration in cerebrospinal fluid was examined at 2 weeks to evaluate the degree of demyelination in patients. RESULTS: MBP concentration was abnormal for almost all patients in Groups P and D, but was not abnormal for any Group A patients. The (mean)Cho/Cr ratios were significantly higher in Groups P and D than in Group A. No significant difference in (mean)NAA/Cr ratio was seen between the three pathological groups and controls. A significant correlation was identified between MBP and (mean)Cho/Cr ratio. CONCLUSIONS: These results suggest that the Cho/Cr ratio in the subacute phase after CO intoxication represents early demyelination in the centrum semiovale, and can predict chronic neurological symptoms.

Iatrogenic hyperammonemia after anorexia.

High-protein dietary supplements were started for 2 patients, who had a period of anorexia before hospital admission but no history of liver disease. Subsequent altered mental status with ataxia developed in both patients. After excluding other causes, hyperammonemia was noted, while liver function test results remained normal. Removal of the high-protein dietary supplements led to reversal of symptoms and normalization of the ammonia level. With the ubiquity of nutrition supplement use outside of liver failure, SHAKE (supplement-associated hyperammonemia after c[k]achetic episode) syndrome may be commonplace in modern hospitals.

Clinical outcomes and low-dose levocarnitine supplementation in psychiatric inpatients with documented hypocarnitinemia: a retrospective chart review.

BACKGROUND: Metabolic encephalopathy is one of the crucial manifestations of carnitine deficiency. In psychiatric patients, low serum carnitine levels may result from chronic valproate therapy. Despite the widespread use of valproate in psychiatry, neither carnitine deficiency nor supplementation has been studied in a psychiatric population. OBJECTIVE: To describe clinical outcomes in hospitalized psychiatric patients with documented hypocarnitinemia who were receiving oral levocarnitine supplementation. METHOD: Retrospective chart review. RESULTS: In 38 patients with hypocarnitinemia, a low-dose oral levocarnitine supplementation, in association with comprehensive psychiatric therapy, did not result in any adverse psychiatric or medical outcomes, and was associated with overall improved behavioral, cognitive, and motor functioning. Initially all patients had some degree of cognitive impairment, but after correction of carnitine serum levels, scores on the Mini-Mental State Examination (MMSE) improved in most of the patients (mean improvement 5.5 points, P <0.0001), and normalized in 11 cases. This allowed a correction of the diagnosis in 8 of 14 patients who had initially been diagnosed with dementia. African-American patients achieved significantly lower serum carnitine levels and MMSE scores than Caucasian patients with comparable therapy. CONCLUSION: We hypothesize that correction of carnitine depletion, either by levocarnitine supplementation or by valproate dose reduction, may enhance recovery from hypocarnitinemia-associated encephalopathy in psychiatric patients. Our findings also suggest that ethnic traits may affect carnitine bioavailability as well as cognitive outcomes in this clinical context. Further studies of carnitine metabolism and supplementation in psychiatric patients are warranted.

Curcumin attenuates diabetic encephalopathy in rats: behavioral and biochemical evidences.

Emerging epidemiological data indicates that diabetes is a potential predisposing factor for neuropsychiatric deficits as stroke, cerebrovascular diseases, diabetic encephalopathy, depression and anxiety. Diabetic encephalopathy, characterized by impaired cognitive functions and neurochemical and structural abnormalities, involves direct neuronal damage caused by intracellular glucose. Curcumin, a well-established phenolic antioxidant and anti-inflammatory molecule, is capable of playing an important role against amyloid and dendritic pathology and thus has neuroprotective properties. The aim of the present study was to explore the effect of curcumin (60 mg/kg; p.o.) on cognitive functions, oxidative stress and inflammation in diabetic rats. Learning and memory behaviors were investigated using a spatial version of the Morris water maze test. Acetylcholinesterase activity, a marker of cholinergic dysfunction, was increased by 80% in the cerebral cortex of diabetic rats. There was 107% and 121% rise in thiobarbituric acid reactive substance levels in cerebral cortex and hippocampus of diabetic rats, respectively. Reduced glutathione level and enzymatic activities of superoxide dismutase and catalase were decreased in both cerebral cortex and hippocampal regions of diabetic rat brain. Nitrite levels in cerebral cortex and hippocampus were increased by 112% and 94% respectively. Serum TNF-alpha, a marker for inflammation, was found to increase by 1100% in diabetic rats. Chronic treatment with curcumin (60 mg/kg; p.o.) significantly attenuated cognitive deficit, cholinergic dysfunction, oxidative stress and inflammation in diabetic rats. The results emphasize the involvement of cholinergic dysfunction, oxidative stress and inflammation in the development of cognitive impairment in diabetic animals and point towards the potential of curcumin as an adjuvant therapy to conventional anti-hyperglycemic regimens for the prevention and treatment of diabetic encephalopathy.

Aspartyl, arginyl and alanyl aminopeptidase activities in the hippocampus and hypothalamus of streptozotocin-induced diabetic rats.

Acid (aspartyl), basic (arginyl) and neutral (alanyl) aminopeptidases degrade angiotensins, vasopressin, oxytocin, bradykinin and enkephalins. These peptides regulate memory, energy homeostasis, water-salt balance and blood pressure, functions that are mainly exerted in the hippocampus and hypothalamus, and that can be affected by diabetes mellitus. To evaluate the relationship between the diabetes mellitus and processing and inactivation roles of these representative aminopeptidases, we measured their activities in both brain structures of control and streptozotocin-diabetic rats. Hypothalamic soluble aspartyl and arginyl aminopeptidases presented significant decreased activity levels in diabetic rats, which were mitigated by insulin therapy. In addition to membrane-bound puromycin sensitive and insensitive alanyl aminopeptidases, its soluble puromycin sensitive form did not differ between diabetic and control rats in both brain structures. Glucose and/or insulin did not seem to alter in vitro the hypothalamic activities of soluble aspartyl and arginyl aminopeptidases. The implied hypothalamic control of regulatory peptide activity by aspartyl and arginyl aminopeptidases supports the hypothesis that the hydrolytic ability of these enzyme types could be a common link for the disruptions of water-salt balance, blood pressure and energy homeostasis in diabetes mellitus.

Neurologic complications of gastric bypass surgery for morbid obesity.

BACKGROUND: The number of bariatric procedures is rapidly growing as the prevalence of obesity in the USA is increasing. Such procedures are not without complications, and those affecting the nervous system are often disabling and irreversible. We now describe our experience with these complications and review the pertinent literature. METHODS: We describe 26 patients with major neurologic conditions that seemed causally related to bariatric surgery encountered in the neurology service of a tertiary referral university medical center over a decade. RESULTS: The neurologic complications affected most regions of the nervous system: encephalopathy, optic neuropathy, myelopathy, polyradiculoneuropathy, and polyneuropathy. Myelopathy was the most frequent and disabling problem; symptoms began about a decade after surgery. Encephalopathy and polyradiculoneuropathy were acute and early complications. Except for vitamin B(12) and copper deficiencies in patients with myelopathy, we could not correlate specific nutritional deficiencies to the neurologic complications. All patients had multiple nutritional deficiencies, but their correction did not often yield dramatic results. The best result was achieved in one patient after surgical revision to reduce the bypassed jejunum. CONCLUSIONS: A wide spectrum of serious neurologic conditions may follow bariatric surgery. These complications may occur acutely or decades later.

Anomalías prenatales asociadas a la deficiencia de yodo / Prenatal anomalies associated with iodine deficiency

Está ampliamente aceptado que las hormonas tiroideas son esenciales para el desarrollo cerebral normal. La deficiencia de yodo en el embarazo conduce a un deterioro del funcionamiento de la glándula tiroidea, tanto materna como fetal. La hipotiroxinemia materna por déficit de yodo en la gestación precoz se asocia frecuentemente a efectos irreversibles sobre el desarrollo neuropsicomotor, incluso si la madre no es clínicamente hipotiroidea.El déficit de yodo distorsiona los patrones migratorios de las células en la corteza cerebral. La citoarquitectura de la corteza somatosensorial y el hipocampo muestran células en localizaciones aberrantes o inapropiadas. Clínicamente, la hipotiroxinemia materna se asocia a secuelas neurológicas, que varían desde una disfunción cerebral mínima hasta un síndrome de discapacidad intelectual grave.Los requerimientos de yodo en la madre están aumentados durante la gestación. Se debe asegurar un adecuado aporte de yodo con el fin de alcanzar la dosis diaria recomendada de 250-300 μg/día. El nacimiento de niños con discapacidad de aprendizaje ya debe prevenirse

It is now widely accepted that thyroid hormones are essential for normal brain development. Iodine deficiency in pregnancy leads to impaired functioning of maternal and fetal thyroid glands. The maternal hypothyroxinemia due to iodine deficiency in early pregnancy is often associated with irreversible effects on neuropsychomotor development, even if the mother is not clinically hypothyroid.Iodine deficiency deranges the migratory patterns of cells into the cortex. The cytoarchitecture in the somatosensory cortex and hippocampus shows cells at aberrants or inappropriate locations. Clinically, maternal hypothyroxinemia is associated with neurological sequels, varying from minimal brain function to a syndrome of severe intellectual disability.The iodine requirements of the mother have to be increased during pregnancy. It is necessary to ensure an adequate iodine supply, in order to achieve the ideal recommended dietary allowance of 250-300 μg/day. The birth of children with learning disabilities must be preventable (AU)

Fatty acid oxidation defects as a cause of neuromyopathic disease in infants and adults.

Fatty acids are a major fuel for the body and fatty acid oxidation is particularly important during fasting, sustained aerobic exercise & stress. The myocardium and resting skeletal muscle utilise long-chain fatty acids as a major source of energy. Inherited disorders of fatty acid oxidation seriously compromise the function of muscle and other highly energy-dependent tissues such as brain, nerve, heart, kidney & liver. Defects of fatty acid oxidation lead to a range of neuromyopathic disease in both adults and children. Such defects encompass a wide spectrum of clinical disease, presenting in the neonatal period or infancy with recurrent hypoketotic hypoglycaemic encephalopathy, liver dysfunction and hyperammonaemia with neurosensory deficits secondary to the acute onset. In addition, there may be cardiac arrhythmias and/or progressive cardiomyopathy, which may give rise to secondary hypoxic-ischaemic encephalopathy. In older children, adolescence or adults there is often exercise intolerance with episodic myalgia or rhabdomyolysis in association with prolonged aerobic exercise or other exacerbating factors. Some disorders are particularly associated with toxic metabolites that may contribute to encephalopathy, polyneuropathy, axonopathy and pigmentary retinopathy. Diagnosis is through clinical suspicion with appropriate investigations in blood and urine taken during crisis. Definitive diagnosis is usually by fibroblast assay. Treatment is generally through avoidance of fasting, frequent carbohydrate rich feeds and in long-chain defects MCT supplementation. Novel treatments include the use of D,L-3-hydroxybutyrate and the potential use of fibrates to increase mutant protein levels in mild disorders.