Neonatal olfactory bulbectomy induces anxiety-related behavior and modifies dopaminergic receptor expression in post-pubertal rats.

Olfaction is a complex physiological process producing effects in the central nervous system (CNS) and implicated in emotional processes. Indeed, the olfactory bulbs (OB) send projections to various CNS regions including the nucleus accumbens (NAcc) and caudate-putamen (CPu). Both the NAcc and CPu receive important dopaminergic input. Emerging evidence suggests that dopamine (DA) is related to anxiety-related behaviors. Therefore, we aimed to investigate the consequences of neonatal olfactory bulbectomy (nOBX) to anxiety-related behavior as assayed in the elevated plus maze (EPM) as well as the expression of dopaminergic receptors (D1-like, D2-like, and D3) in the NAcc and CPu at pre- and post-pubertal ages in the rat. The results show that nOBX increased the number of entries in the open arm of the EPM post-pubertally, suggesting an anxiolytic-related effect. nOBX increased the D2-like binding in the NAcc shell and D3 binding in the NAcc core pre-pubertally. At post-pubertal ages, the D3 binding was reduced at the olfactory tubercle and islands of Calleja in nOBX rats. Alterations in the DA receptor expression may be one mechanism responsible for the observed behavioral modifications in nOBX rats.

Persistent peripheral inflammation and pain induces immediate early gene activation in supraspinal nuclei in rats.

Pain is a public health concern worldwide and can present simultaneously with anxiety and depression. c-Fos is a marker used to identify activated cells in response to various stimuli. Specifically, it can be used as a brain marker of pain. We examined whether peripheral inflammation produces mechanical allodynia, anxiety- and depression-related behaviors in male rats (Rattus norvegicus, Wistar strain) and if these behaviors can have an impact on c-Fos expression in the supraspinal nuclei involved in pain control. We assessed mechanical thresholds by von Frey monofilaments, depression-like behaviors in the forced swimming test (FST) and anxiety-related behaviors in the open field test (OFT) after the administration of the inflamogen Complete Freund´s Adjuvant (CFA) in rats. We found that CFA increased paw diameter is all rats, however, CFA treatment resulted in a subgroup of rats developing allodynia [CFA- mechanical allodynia (CFA-MA)] and a subgroup of rats not developing allodynia [CFA-no mechanical allodynia (CFA-NMA)]. The peak of tactile allodynia and inflammation were coupled with an increase in c-Fos expression in several supraspinal brain nuclei, i.e. basolateral amygdala, periaqueductal gray matter and rostroventromedial medulla in CFA-MA rats. Moreover, we found a correlation between c-Fos levels and mechanical thresholds. No modification in c-Fos expression was observed in CFA-NMA rats. CFA did not modulate behaviors in the OFT or FST. In summary, we show that mechanical allodynia but not peripheral inflammation activates c-Fos in several supraspinal nuclei, which sheds new light on brain regions involved in the control of pain following peripheral injury and decouples this effect from mere peripheral inflammation. This model may be used to study resistance to pain development in future studies.

Evidence for Endogenous Opioid Dependence Related to Latent Sensitization in a Rat Model of Chronic Inflammatory Pain.

Studies performed in a mouse model of chronic inflammatory pain induced by intraplantar injection of complete Freund's adjuvant (CFA) have shown that constitutive activation of the endogenous opioid signaling, besides serving as a mechanism of endogenous analgesia that tonically represses pain sensitization, also generates a state of endogenous opioid dependence. Since species-related differences concerning pain biology and addictive behaviors occur between mice and rats, the present study explored whether the coexistence of endogenous opioid analgesia and endogenous opioid dependence also characterizes a homologous rat model. To this aim, CFA-injured Wistar rats were treated with either 3 mg/kg or 10 mg/kg of the opioid receptor inverse agonist naltrexone (NTX) during the pain remission phase and monitored for 60 min for possible withdrawal behaviors. At 3 mg/kg, NTX, besides inducing the reinstatement of mechanical allodynia, also caused a distinct appearance of ptosis, with slight but nonsignificant changes to the occurrence of teeth chatters and rearing. On the other hand, 10 mg/kg of NTX failed to unmask pain sensitization and induced significantly lower levels of ptosis than 3 mg/kg. Such an NTX-related response pattern observed in the rat CFA model seems to differ substantially from the pattern previously described in the mouse CFA model. This supports the knowledge that mice and rats are not identical in terms of pharmacological response and stresses the importance of choosing the appropriate species for preclinical pain research purposes depending on the scientific question being asked.

Cellular mechanisms in brain aging: Focus on physiological and pathological aging.

Aging is a natural phenomenon characterized by accumulation of cellular damage and debris. Oxidative stress, cellular senescence, sustained inflammation, and DNA damage are the main cellular processes characteristic of aging associated with morphological and functional decline. These effects tend to be more pronounced in tissues with high metabolic rates such as the brain, mainly in regions such as the prefrontal cortex, hippocampus, and amygdala. These regions are highly related to cognitive behavior, and therefore their atrophy usually leads to decline in processes such as memory and learning. These cognitive declines can occur in physiological aging and are exacerbated in pathological aging. In this article, we review the cellular processes that underlie the triggers of aging and how they relate to one another, causing the atrophy of nerve tissue that is typical of aging. The main topic of this review to determine the central factor that triggers all the cellular processes that lead to cellular aging and discriminate between normal and pathological aging. Finally, we review how the use of supplements with antioxidant and anti-inflammatory properties reduces the cognitive decline typical of aging, which reinforces the hypothesis of oxidative stress and cellular damage as contributors of physiological atrophy of aging. Moreover, cumulative evidence suggests their possible use as therapies, which improve the aging population's quality of life.

A nutraceutical formulation combined with sclerofoam-assisted laser treatment ameliorates chronic venous insufficiency.

Chronic venous insufficiency has a high impact on the healthcare system due to its high incidence worldwide. We performed a study in 30 women with thigh and leg varices due to major saphenous vein valve incontinence with saphenous trunk reflux causing phlebo-lymphoedema to assess the efficacy of sclerofoam-assisted laser treatment combined with nutraceutical administration. The patients underwent endovascular combination sealing of the saphenous trunk with sclerofoam-assisted laser treatment technique into the major saphenous veins under low-volume tumescent anesthesia followed by intraoperative phlebectomies. Post-operatively, the patients received capsules containing Aesculus Hippocastanum, chondroitin sulphate, proanthocyanidins from Pinus pinaster Aiton, proanthocyanidins from Vitis vinifera L., hydrolysed marine collagen and carcinine dihydrochloride for 3 weeks. We evaluated the extracellular fluid volume of the lower limbs using bioimpedance spectroscopy pre- (T0) and post-surgery (T2) (impedance is a vector which is composed of two components, resistance [RES] and reactance [REA)]). In addition, we evaluated the following parameters pre- and post-surgery: pain, heaviness, paresthesia, itching, swelling, daily urine volume output and leg volume. Limb volume was significantly decreased at T2 compared to T0 (p < 0.01). RES and REA were significantly increased at T2 compared to T0 (p < 0.0001 and p < 0.01, respectively). A significant improvement in heaviness, paresthesia, pain, swelling and itch was also observed (all p < 0.0001) while no changes in terms of diuresis occurred. No adverse effects were observed. The present study shows a promising approach to the treatment of chronic venous insufficiency that warrants further clinical studies in larger cohorts of patients.

Comparison between an Emerging Point-of-Care Tool for TSH Evaluation and a Centralized Laboratory-Based Method in a Cohort of Patients from Southern Italy.

Endocrine and metabolic disorders are a common condition in Europe and worldwide, and, among these, thyroid dysfunction still remains a problem. The measurement of thyroid stimulating hormone (TSH) levels represents the first-line assay for the assessment of thyroid function. In the present study, we compared serum concentrations of TSH, measured using a commercially available point-of-care test (POCT) method (FastPack® IP) and an established "conventional" laboratory-based method (Beckmann Access 2) in a cohort of patients from Foggia in Southern Italy. A strong correlation (r = 0.994) was found between both methods and was also confirmed by receiver operating characteristic (ROC) curve analysis (0.82). The within-run coefficient of variation (CV) using FastPack® ranged from 4.03% and 8.57% at the TSH concentrations of 39.49 and 0.70 mIU/L, respectively. The between-run CV was 10.34% and 6.33% at the TSH concentrations of 0.87 and 26.55 mIU/L, respectively. The ratios of within- to between-assay CV were 0.83 and 1.06 at the TSH levels of 0.70 and 52.59 mIU/mL, respectively. In this study, we showed that serum TSH levels can be measured in a few minutes and at low-cost in terms of materials and equipment required. We observed that this approach is user-friendly, accurate, reproducible, and suitable for use in the clinic, while also meeting the criteria for effectiveness, impact, efficiency, and sustainability.

Serum miR-96-5P and miR-339-5P Are Potential Biomarkers for Multiple System Atrophy and Parkinson's Disease.

Parkinson's disease (PD) and Multiple System Atrophy (MSA) are progressive neurodegenerative diseases with overlap of symptoms in early stages of disease. No reliable biomarker exists and the diagnosis is mainly based on clinical features. Several studies suggest that miRNAs are involved in PD and MSA pathogenesis. Our goal was to study two serum circulating microRNAs (miR-96-5p and miR-339-5p) as novel biomarkers for the differential diagnosis between PD and MSA. Serum samples were obtained from 51 PD patients, 52 MSA patients and 56 healthy controls (HC). We measured levels of miRNAs using quantitative PCR and compared the levels of miR-96-5p and miR-339-5p among PD, MSA and HC groups using a one-way analysis of variance. Correlations between miRNA expression and clinical data were calculated using Pearson's rho test. We used the miRTarBase to detect miRNA targets and STRING to evaluate co-expression relationship among target genes. MiR-96-5p was significantly increased in MSA patients compared with HC (Fold change (fc): 3.6; p = 0.0001) while it was decreased in PD patients compared with HC (Fold change: 4; p = 0.0002). Higher miR-96-5P levels were directly related to longer disease duration in MSA patients. We observed a significant increase of miR-339-5p in MSA patients compared with PD patients (fc: 2.5; p = 0.00013). miR-339-5p was increased in MSA patients compared with HC (fc: 2.4; p = 0.002). We identified 32 target genes of miR-96-5p and miR-339-5p, some of which are involved in neurodegenerative diseases. The study of those miRNAs could be useful to identify non-invasive biomarkers for early differential diagnosis between PD and MSA.

New insights on nitric oxide: Focus on animal models of schizophrenia.

Schizophrenia is a devastating complex disorder characterised by a constellation of behavioral deficits with the underlying mechanisms not fully known. Nitric oxide (NO) has emerged as a key signaling molecule implicated in schizophrenia. Three nitric oxide sinthases (NOS), endothelial, neuronal, and inducible, release NO within the cell. Animal models of schizophrenia are grouped in four groups, neurovedelopmental, glutamatergic, dopaminergic and genetic. In this review, we aim to evaluate changes in NO levels in animal models of schizophrenia and the resulting long-lasting behavioral and neural consequences. In particular, NO levels are substantially modified, region-specific, in various neurodevelopmental models, e.g. bilateral excitotoxic lesion of the ventral hippocampus (nVHL), maternal immune activation and direct NO manipulations early in development, among others. In regards to glutamatergic models of schizophrenia, phencyclidine (PCP) administration increases NO levels in the prefrontal cortex (PFC) and ventral hippocampus. As far as genetic models are concerned, neuronal NOS knock-out mice display schizophrenia-related behaviors. Administration of NO donors can reverse schizophrenia-related behavioral deficits. While most modifications in NO are derived from neuronal NOS, recent evidence indicates that PCP treatment increases NO from the inducible NOS isoform. From a pharmacological perspective, treatment with various antipsychotics including clozapine, haloperidol and risperidone normalize NO levels in the PFC as well as improve behavioral deficits in nVHL rats. NO induced from the neuronal and inducible NOS is relevant to schizophrenia and warrants further research.

The role of sensory and olfactory pathways in multiple chemical sensitivity.

Multiple chemical sensitivity (MCS) is characterised by non-specific and recurring symptoms affecting multiple organs and associated with exposure to chemicals, even at low concentrations, which are, under normal circumstances, harmless to the general population. Symptoms include general discomfort, cardiovascular instability, irritation of the sensory organs, breath disorders, hypersensitivity affecting the skin and epithelial lining of the gut, throat and lungs, anxiety, and learning and memory loss. Chemical intolerance is a key distinguishing feature of MCS, limiting considerably patients' lifestyle with serious social, occupational and economic implications. Since no specific diagnostic markers are currently available for chemical intolerance, the diagnosis relies on clinical symptoms. Despite the formulation of several hypotheses regarding the pathophysiology of MCS, its mechanisms remain undefined. A person-centred care approach, based on multidisciplinary and individualised medical plans, has shown promising results. However, more definite treatment strategies are required. We have reviewed the main experimental studies on MCS pathophysiology, focusing on the brain networks involved, the impact of environmental pollution on the olfactory system and the correlation with other pathologies such as neurodegenerative diseases. Finally, we discuss treatment strategies targeting the olfactory system.

Natural products present neurotrophic properties in neurons of the limbic system in aging rodents.

Aging is a complex process that can lead to neurodegeneration and, consequently, several pathologies, including dementia. Physiological aging leads to changes in several body organs, including those of the central nervous system (CNS). Morphological changes in the CNS and particularly the brain result in motor and cognitive deficits affecting learning and memory and the circadian cycle. Characterizing neural modifications is critical to designing new therapies to target aging and associated pathologies. In this review, we compared aging to the changes occurring within the brain and particularly the limbic system. Then, we focused on key natural compounds, apamin, cerebrolysin, Curcuma longa, resveratrol, and N-PEP-12, which have shown neurotrophic effects particularly in the limbic system. Finally, we drew our conclusions delineating future perspectives for the development of novel natural therapeutics to ameliorate aging-related processes.

Repeated administration of a flavonoid-based formulated extract from citrus peels significantly reduces peripheral inflammation-induced pain in the rat.

Depression-related disorders are the first cause of disability worldwide according to the World Health Organization, and there is limited availability of effective antidepressant medications without side effects. Similarly, pain management is a public health concern particularly due to the increase in use of opioid medications, which have a significant side effect profile. Flavonoids can modulate numerous physiological functions including emotional and anti-nociceptive processes. Gold lotion (GL) is a natural product based on the extract of six citrus peels rich in flavonoids (0.45 mg/ml) with numerous reported biological activities. In the present study, we investigated the effect of repeated administration of GL in a battery of behavioral tests, including the open field test (OFT), forced swim test (FST), and von Frey test (vFT), in rats. While the OFT measured anxiolytic-related effects, the FST evaluated depression-related behavior. The vFT evaluated mechanical allodynia in two rat models of peripheral inflammation induced by carrageenan or complete Freund's adjuvant (CFA) administration. Treatment with GL reduced mechanical allodynia after either carrageenan or CFA administration. On the other hand, repeated GL administration did not modulate any behavior evaluated by OFT or FST. Consumption of GL inhibits behavioral signs of inflammatory pain. Therefore, GL may be a valuable analgesic product to be used for inflammatory pain.

Monocentric single-arm study of desmopressin acetate efficacy on nocturnal polyuria in the elderly.

AIM OF THE STUDY: We designed a retrospective, monocentric, observational study to assess the efficacy and short-term side effect profile of desmopressin, a synthetic analogue of antidiuretic hormone, in 42 elderly patients affected by nocturnal polyuria (NP), a subset of nocturia (nocturnal overproduction of urine at night), which is characterised by nocturnal urine volume (NVU) exceeding 33% of the 24-hours total urine output. METHODS USED TO CONDUCT THE STUDY: The subjects had NP and included 25 males, which had benign prostatic hyperplasia (12 out of 25 had been surgically or endoscopically operated) and 15 females that had increased urinary frequency, night-time voiding, loss of bladder control and recurrent bladder infections, due to perineal wall weakness and vaginal or bladder prolapse. Patients recorded the number of voids during waking hours using a digital continuous urine meter. The quality of life (QoL) and efficacy of desmopressin were assessed at baseline and 12 weeks after treatment using the International Consultation on Incontinence Questionnaire Nocturia Quality of Life Module (ICIQ-Nqol) and International Prostate Symptom Score questionnaire (IPPS-Q8). The dosage of desmopressin acetate varied according to the discretion of the physician, usually beginning with one tablet before going to bed at night for 3 months. The dose was increased at 1-week intervals if a reduction in the NVU or night-time frequency was not achieved. RESULTS OF THE STUDY: We found that desmopressin treatment reduced the nocturnal voided volume (P < .0001), ICIQ-Nqol (P < .0001) and IPPS-Q8 (P < .0001). No significant serum sodium alterations or modifications in serum creatine, potassium, or body weight were observed in all the patients. No adverse effects were observed. CONCLUSIONS DRAWN FROM THE STUDY AND CLINICAL IMPLICATIONS: Our findings show efficacy of desmopressin in the elderly for NP treatment supporting further clinical trials in larger cohorts of patients.

Cosmetic penile enhancement surgery: a 3-year single-centre retrospective clinical evaluation of 355 cases.

Men's satisfaction and sexual function is influenced by discomfort over genital size which leads to seek surgical and non-surgical solutions for penis alteration. In this article we report the results of a retrospective study of 355 cases of cosmetic elongation, enlargement and combined elongation and enlargement phalloplasty. We found a significant improvement in length at rest, stretched length and circumference at rest at 2, 6 and 12 months post-surgical procedure (all p < 0.0001). 5-item International Index of Erectile Function (IIEF-5) was also increased at 12 months post-surgery compared to baseline (p < 0.0001). This was consistent with an IIEF-5 improvement of 6.74% compared to baseline. This study is clinically relevant due to the large cohort of patients included and because it is the first study to use an inverse periosteal-fascial suture not described previously as part of the surgical methodology.

Cerebrolysin improves peripheral inflammatory pain: Sex differences in two models of acute and chronic mechanical hypersensitivity.

Chronic inflammatory pain is a major health problem worldwide with high prevalence in women. Cerebrolysin is a multimodal neuropeptide preparation that crosses the blood brain barrier and displays neuroprotective properties in aging and disease. Previously, we showed that cerebrolysin reduced mechanical allodynia in a model of persistent inflammation and pain. We aim to build upon the findings of our previous study by investigating the response to acute administration of cerebrolysin in two models of peripheral inflammation and assessing sex differences. We utilized the complete Freund's adjuvant (CFA) that produces maximal oedema and mechanical allodynia within days and carrageenan that produces similar effects within hours. Cerebrolysin reversed the mechanical allodynia in both sexes in CFA-treated rats. On the other hand, in rats treated with carrageenan, cerebrolysin was only effective in reducing mechanical allodynia in female rats. In conclusion, the present study shows that cerebrolysin effects may be sex-specific depending on different mechanisms that are at play in these two models of peripheral inflammatory pain. Further investigations are required to determine the factors contributing to sex differences.

Serum miR-30c-5p is a potential biomarker for multiple system atrophy.

Multiple system atrophy (MSA) is a neurodegenerative disease that belongs to the α synucleinopathies. Clinically, there is an overlap between MSA and Parkinson's disease (PD), especially at the early disease stage. However, these two pathologies differ in terms of disease progression. Currently, no biomarker exists to differentiate MSA from PD. MicroRNAs are non-coding RNAs implicated in gene expression regulation. MiRNAs modulate cellular activity and they control a range of physiological and pathological functions. miRNAs are found in biofluids, such as blood, serum, plasma, saliva, and cerebrospinal fluid. Many groups, including ours, found that circulating miRNAs are differently expressed in blood, plasma, serum and cerebrospinal fluid of PD and MSA patients. In the present study, our primary aim was to determine if serum mir-30-5p and mir-148b-5p can be used as biomarkers for early diagnosis of PD and/or MSA. Our secondary goal was to determine if serum levels of those miRNAs can be correlated with the patients' clinical profile. Using quantitative PCR (qPCR), we evaluated expression levels of miR-30c-5p and miR148b-5p in serum samples from PD (n = 56), MSA (n = 49), and healthy control (n = 50) subjects. We have found that miR-30c-5p is significantly upregulated in MSA if compared with PD and healthy control subjects. Moreover, serum miR-30c-5p levels correlate with disease duration in both MSA and PD. No significant difference was found in miR-148b-5p among MSA, PD and healthy control subjects. Our results suggest a possible role of serum miR-30-5p as a biomarker for diagnosis and progression of MSA.

Prenatal immune challenge induces behavioral deficits, neuronal remodeling, and increases brain nitric oxide and zinc levels in the male rat offspring.

Schizophrenia is a severe mental disorder with numerous etiological susceptibilities. Maternal infection is a key risk factor for schizophrenia. Prenatal lipopolysaccharide (LPS) infection stimulates cytokine production that affects brain development. In the present study, we aimed to investigate the effect of prenatal LPS injection at gestational day (GD) 14-16 on behavioral paradigms, and neuronal morphology in the prefrontal cortex (PFC), basolateral amygdala (BLA), nucleus accumbens (NAcc) and ventral hippocampus (VH) at two critical ages of development: pre-pubertal (postnatal day 35, PD35) and post-pubertal (PD60) age in male rats. We also evaluated the effects of LPS on nitric oxide (NO) and zinc (Zn) levels in seven brain areas (PFC, VH, amygdala, brainstem, striatum and dorsal hippocampus) at PD35 and PD60. LPS induced hyperlocomotion in a novel environment and reduced social contact as well as increased the levels of NO and Zn in the PFC, brainstem and amygdala as observed in other animal models of schizophrenia-related behavior. Furthermore, we found that LPS-treated rats presented post-pubertal neuronal hypertrophy in the PFC and BLA and decreased spine density in the NAcc. The neuronal morphology of neurons in the VH in LPS-treated rats remained unaltered. Interestingly, the anxiogenic-related behavior correlated with neuronal hypertrophy observed in the BLA. Our findings suggest that the behavioral and neural modifications observed in our model could be mediated by the long-lasting alterations in Zn and NO levels in the brain.

Role of proteoglycans and glycosaminoglycans in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an inherited fatal X-linked myogenic disorder with a prevalence of 1 in 3500 male live births. It affects voluntary muscles, and heart and breathing muscles. DMD is characterized by continuous degeneration and regeneration cycles resulting in extensive fibrosis and a progressive reduction in muscle mass. Since the identification of a reduction in dystrophin protein as the cause of this disorder, numerous innovative and experimental therapies, focusing on increasing the levels of dystrophin, have been proposed, but the clinical improvement has been unsatisfactory. Dystrophin forms the dystrophin-associated glycoprotein complex and its proteins have been studied as a promising novel therapeutic target to treat DMD. Among these proteins, cell surface glycosaminoglycans (GAGs) are found almost ubiquitously on the surface and in the extracellular matrix (ECM) of mammalian cells. These macromolecules interact with numerous ligands, including ECM constituents, adhesion molecules and growth factors that play a crucial role in muscle development and maintenance. In this article, we have reviewed in vitro, in vivo and clinical studies focused on the functional role of GAGs in the pathophysiology of DMD with the final aim of summarizing the state of the art of GAG dysregulation within the ECM in DMD and discussing future therapeutic perspectives.

Feasibility single-arm study of a medical device containing Desmodium adscendens and Lithothamnium calcareum combined with chemotherapy in head and neck cancer patients.

BACKGROUND: Neoplasms of the head and neck represent approximately 5% of cancers and they require complex multidisciplinary clinical management. Desmodium adscendens (Desmodium) is a plant that possesses anti-allergic, antioxidant and hepatoprotective properties. Lithothamnium calcareum (Lithothamnium) is a calcified seaweed that possesses remineralization properties and the ability to maintain homeostasis. AIM: In this single-arm study, we investigated the efficacy of a combination therapy based on Desmovit® which contains Desmodium and Lithothamnium, and chemotherapy in patients with head and neck cancer. METHODS: Twelve patients with histological or cytological diagnosis of stage IV head and neck cancer were enrolled in this study that was approved by the ethics committee of the Unità Operativa Complessa (UOC) di Oncologia Medica Azienda Ospedaliera Ospedali Riuniti Marche Nord and followed the Declaration of Helsinki guidelines. The patients were monitored by investigation of the performance status according to the Glasgow Prognostic Score (GPS), which evaluates the plasma level of C-reactive protein and albumin levels, and the Eastern Cooperative Oncology Group (ECOG) examination. Pain and fatigue were also monitored using the visual analog scale and visual analog fatigue scale, respectively. All the above parameters were assessed biweekly to week 10. RESULTS: GPS, ECOG, and albumin remained stable throughout the study with a trend towards a decrease in GPS and albumin at week 10 post-treatment. Pain significantly improved at week 8 (P<0.05) while fatigue improved at weeks 8 and 10 (all P<0.01). CONCLUSION: We found that chemotherapy, combined with Desmodium and Lithothamnium, improved pain and fatigue in head and neck cancer patients, although we cannot confirm if this was due to Desmodium and Lithothamnium or chemotherapy. The improvement in pain and fatigue was supported by the ECOG performance status remaining stable with the highest score being equal to 2 throughout the study and a trend towards an improvement in GPS performance status and albumin levels.

Translating SOD1 Gene Silencing toward the Clinic: A Highly Efficacious, Off-Target-free, and Biomarker-Supported Strategy for fALS.

Of familial amyotrophic lateral sclerosis (fALS) cases, 20% are caused by mutations in the gene encoding human cytosolic Cu/Zn superoxide dismutase (hSOD1). Efficient translation of the therapeutic potential of RNAi for the treatment of SOD1-ALS patients requires the development of vectors that are free of significant off-target effects and with reliable biomarkers to discern sufficient target engagement and correct dosing. Using adeno-associated virus serotype 9 to deliver RNAi against hSOD1 in the SOD1G93A mouse model, we found that intrathecal injection of the therapeutic vector via the cisterna magna delayed onset of disease, decreased motor neuron death at end stage by up to 88%, and prolonged the median survival of SOD1G93A mice by up to 42%. To our knowledge, this is the first report to demonstrate no significant off-target effects linked to hSOD1 silencing, providing further confidence in the specificity of this approach. We also report the measurement of cerebrospinal fluid (CSF) hSOD1 protein levels as a biomarker of effective dosing and efficacy of hSOD1 knockdown. Together, these data provide further confidence in the safety of the clinical therapeutic vector. The CSF biomarker will be a useful measure of biological activity for translation into human clinical trials.

A nutraceutical diet based on Lespedeza spp., Vaccinium macrocarpon and Taraxacum officinale improves spontaneous feline chronic kidney disease.

Chronic kidney disease is characterized by structural and/or functional impairment of one or both kidneys persisting for more than 3 months. In cats, chronic kidney disease can frequently occur in animals aged over 9 years with an incidence of approximately 10%. Thirty-four client-owned, neutered cats, suffering from stage II-III chronic kidney disease and diagnosed according to the International Renal Interest Society guidelines were randomly assigned to receive either a control diet (n = 17) or a nutraceutical diet (ND; n = 17) for 90 days. Both diets were commercialized for management of CKD symptoms. The diets were identical except that the ND contained tablets that consisted of 60-80% hydrolysed proteins, 20-40% minerals and active substances, that are, Lespedeza spp. 0.0588%, Vaccinium macrocarpom 0.0371%, and Taraxacum officinale 0.0231%. No adverse effects were reported during this study. Both diets resulted in an improvement in CKD symptoms. After a 90-day evaluation, creatinine, blood urea nitrogen, total proteins, and aspartate aminotransferase significantly decreased in cats that received the ND. A significant decrease was also observed in urine turbidity score, color score, and total proteins in cats that received the ND. We have found that a ND based on Lespedeza spp., Vaccinium macrocarpon, and Taraxacum officinale improves key indicators of renal failure in cats affected by chronic kidney disease.