Cachexia: Pathophysiology and Ghrelin Liposomes for Nose-to-Brain Delivery.

Cachexia, a severe multifactorial condition that is underestimated and unrecognized in patients, is characterized by continuous muscle mass loss that leads to progressive functional impairment, while nutritional support cannot completely reverse this clinical condition. There is a strong need for more effective and targeted therapies for cachexia patients. There is a need for drugs that act on cachexia as a distinct and treatable condition to prevent or reverse excess catabolism and inflammation. Due to ghrelin properties, it has been studied in the cachexia and other treatments in a growing number of works. However, in the body, exogenous ghrelin is subject to very rapid degradation. In this context, the intranasal release of ghrelin-loaded liposomes to cross the blood-brain barrier and the release of the drug into the central nervous system may be a promising alternative to improve its bioavailability. The administration of nose-to-brain liposomes for the management of cachexia was addressed only in a limited number of published works. This review focuses on the discussion of the pathophysiology of cachexia, synthesis and physiological effects of ghrelin and the potential treatment of the diseased using ghrelin-loaded liposomes through the nose-to-brain route.

[A family with Allan-Herndon-Dudley syndrome due to SLC16A2 gene mutation].

Objective: To report a family diagnosed with Allan-Herndon-Dudley syndrome (AHDS) due to SLC16A2 gene mutation and to summarize the phenotypes, genotypes, diagnosis, treatment, and prognosis. Methods: The clinical features of a family of AHDS diagnosed in Xiangya Hospital of Central South University in November 2017 were analyzed. Related literature was searched at Online Mendelian Inheritance in Man (OMIM), PubMed, CNKI and Wanfang database (from the establishment of databases to June 2018) by using "Allan-Herndon-Dudley syndrome" , and "AHDS" as keywords and the case reports from April 2013 to June 2018 were reviewed. Results: The proband was a boy aged 8 months who presented with global developmental retardation, inability to hold up the head, disability to sit independently or grab, no language development, elongated face, big ears, esotropia, scoliosis, hypotonia in the trunk, hypertonia in extremities, and hyperreflexia. Brain magnetic resonance imaging (MRI) showed widening of the extracerebral space and delayed myelination. Thyroid function tests revealed increased FT3, decreased FT4 and normal TSH. Whole exome sequencing (WES) revealed the SLC16A2 gene c.431-1 (IVS1) G>C hemizygous mutation. The infant's mother and grandmother are carriers, but whose father had no related mutation. One uncle from maternal side had severe psychomotor retardation as well as dystonia and died at one year of age with unknown etiology. A total of 97 articles were retrieved in which 19 case reports were reviewed. Forty-two cases (22 from 8 families and 20 sporadic) were reported. Among these 42 cases (all males), all of them presented with moderate to severe cognitive dysfunction, 15 with seizures; 36 were bedridden, only 4 could walk; 31 had no language development, 2 could speak sentences, 4 could speak few words, 1 had babbling sounds. Furthermore,16 had microcephaly, 18 had facial dysmorphism, 6 had esotropia, 2 had hearing loss,14 had scoliosis, 11 had joint contracture, 30 had low body weight/muscle wasting, 37 had hypotonia in trunk or extremities, 32 had progressive spastic paraplegia or hypertonia. In terms of thyroid function, 33 had abnormal results, within whom 30 had increased T3, 25 had decreased T4 and 3 had increased TSH. Brain MRI showed delayed myelination in 22 cases, within which one normalized with development. Genetic tests showed that 31 had missense mutation (14 sporadic), 5 had deletion mutation (3 sporadic, and 1 due to frameshift mutation), 5 had insertion mutation (2 sporadic), and 1 had repeated mutation. The prognosis was poor as patients often died of recurrent respiratory tract infection. Conclusions: The main clinical manifestations of AHDS are severe global developmental retardation, hypotonia, spastic paraplegia, abnormal serum levels of thyroid hormone and delayed brain myelination. SLC16A2 c. 431-1 (IVS1) G > C mutation is accountable for this disease.

Aldosterone (mineralocorticoid) equivalent to prednisolone (glucocorticoid) in reversing hearing loss in MRL/MpJ-Fas1pr autoimmune mice.

HYPOTHESIS: Although the glucocorticoid prednisone is the standard therapy for autoimmune sensorineural hearing loss, what this hormone does in the ear to restore hearing is not known. MRL/MpJ-Fas(lPr) autoimmune mice consistently have shown only stria vascularis disease, implying that abnormal ion balances in the endolymph underlie cochlear dysfunction. Previously we have shown that hearing loss in these mice is reversed with prednisolone treatment. This, coupled with the complete lack of cochlear inflammation, suggests that the restoration of hearing with prednisolone is due to its sodium transport function and not to its anti-inflammatory or immune suppression effects. Therefore the hypothesis of this study was that the mineralocorticoid aldosterone, which only increases sodium transport, would be as effective as prednisolone in reversing autoimmune hearing loss. STUDY DESIGN: MRL/MpJ-Fas(lPr) autoimmune mice were treated with either prednisolone or aldosterone to compare steroid effects on auditory brainstem response (ABR) thresholds and stria morphology. METHODS: After baseline ABR audiometry, autoimmune mice were given prednisolone (5 mg/kg per day), aldosterone (15 microg/kg per day), or water in their drinking bottles. After 2 months of treatment the ABR thresholds were remeasured, and ears collected for histological examination. RESULTS: The untreated controls showed continued elevation of ABR thresholds and edematous stria. However, thresholds in most steroid mice were improved or unchanged and their stria morphology improved, particularly with aldosterone treatment. CONCLUSIONS: Restoration of hearing with steroid treatment is due to increased sodium transport to re-establish cochlear ionic balances. Aldosterone therapy may offer advantages over prednisone for long-term management of not only autoimmune hearing loss, but also other forms of nonimmune-related deafness for which steroids are currently prescribed.