An update on clinical presentation and responses to therapy of patients with hereditary hypophosphatemic rickets with hypercalciuria (HHRH).

Pathogenic variants in solute carrier family 34, member 3 (SLC34A3), the gene encoding the sodium-dependent phosphate cotransporter 2c (NPT2c), cause hereditary hypophosphatemic rickets with hypercalciuria (HHRH). Here, we report a pooled analysis of clinical and laboratory records of 304 individuals from 145 kindreds, including 20 previously unreported HHRH kindreds, in which two novel SLC34A3 pathogenic variants were identified. Compound heterozygous/homozygous carriers show above 90% penetrance for kidney and bone phenotypes. The biochemical phenotype for heterozygous carriers is intermediate with decreased serum phosphate, tubular reabsorption of phosphate (TRP (%)), fibroblast growth factor 23, and intact parathyroid hormone, but increased serum 1,25-dihydroxy vitamin D, and urine calcium excretion causing idiopathic hypercalciuria in 38%, with bone phenotypes still observed in 23% of patients. Oral phosphate supplementation is the current standard of care, which typically normalizes serum phosphate. However, although in more than half of individuals this therapy achieves correction of hypophosphatemia it fails to resolve the other outcomes. The American College of Medical Genetics and Genomics score correlated with functional analysis of frequent SLC34A3 pathogenic variants in vitro and baseline disease severity. The number of mutant alleles and baseline TRP (%) were identified as predictors for kidney and bone phenotypes, baseline TRP (%) furthermore predicted response to therapy. Certain SLC34A3/NPT2c pathogenic variants can be identified with partial responses to therapy, whereas with some overlap, others present only with kidney phenotypes and a third group present only with bone phenotypes. Thus, our report highlights important novel clinical aspects of HHRH and heterozygous carriers, raises awareness to this rare group of disorders and can be a foundation for future studies urgently needed to guide therapy of HHRH.

Psychosocial interventions for teenagers with adolescent idiopathic scoliosis: A systematic literature review.

OBJECTIVES: Psychosocial interventions can improve teenagers' self-esteem, mental health and bracing compliance. There is a need to compile available evidence of psychosocial care in adolescent idiopathic scoliosis. This systematic review aimed to identify and evaluate the effects of existing interventional studies of psychosocial care for the adolescent idiopathic scoliosis population. METHODS: A comprehensive search of relevant literature published from the inception to March 2023 was conducted using nine databases. A google scholar search was performed on 1 July 2023, to update the searching results. Two reviewers independently assessed the methodological quality and extracted details of the included studies. Given the heterogeneity of the selected articles, the findings were synthesized narratively without conducting a meta-analysis. RESULTS: Four randomized controlled trials reported in six articles involving 385 teenagers were included. The interventions appeared acceptable with high recruitment rates and low dropout rates reported. Psychosocial interventions had shown significant positive effects on postoperative pain, engagement in daily and social activities as well as brace use, coping abilities and anxiety. CONCLUSION: Psychosocial interventions are generally feasible and acceptable among the adolescent idiopathic scoliosis population and have produced positive effects on a variety of physical and psychosocial outcomes. Study findings need to be interpreted with caution due to the limited number of available articles and the methodological concerns of the reviewed articles. PRACTICAL IMPLICATIONS: Well-designed clinical trials are warranted in people from cultural backgrounds to develop and implement effective psychosocial interventions for teenagers with adolescent idiopathic scoliosis, not only for those at the post-surgery stage but also for those receiving conservative treatment.

Treatment Response of Sacrococcygeal Chordoma to Palliative Stereotactic Body Radiotherapy: A Case Report.

Chordomas are rare and locally aggressive tumours that arise from embryonic remnants of the notochord, with a predilection for the skull base, mobile spine, and sacrum. Sacral or sacrococcygeal chordomas can be particularly difficult to manage because of their large size at presentation and involvement of adjacent organs and neural structures. Although the recommended definitive therapy for such tumours is either en bloc resection with or without adjuvant radiotherapy (RT) or definitive fractionated RT with charged particle therapy, older and/or less-fit patients may not necessarily be accepting of said approaches due to the potential morbidities and challenging logistic requirements. Here, we report a case of a 79-year-old male presenting with intractable lower limb pain and neurologic deficits due to a large de novo sacrococcygeal chordoma. The patient was successfully treated with a 5-fraction course of stereotactic body radiotherapy (SBRT), given with palliative intent, with complete relief of his symptoms achieved approximately 21 months after RT and without the development of any iatrogenic toxicities. In view of this case, ultra-hypofractionated SBRT may be a suitable option for the palliation of large de novo sacrococcygeal chordomas for selected patients to reduce their symptom burden and improve their quality of life.

Cross-Cultural Adaptation and Psychometric Validation of the Constipation Assessment Scale among Chinese Adult Psychiatric Patients.

BACKGROUND: Constipation is a functional gastrointestinal disorder that presents with signs and symptoms, which are typically assessed subjectively. Various measurement scales, such as the Constipation Assessment Scale (CAS), are commonly used to evaluate constipation among the general population. However, the instruments should be culturally and contextually relevant in adult psychiatric patients to generate valid and reliable evidence. PURPOSE: This study aimed to cross-culturally adapt and psychometrically validate the traditional Chinese version of the CAS among adult psychiatric patients in Hong Kong. METHOD: Using the Brislin protocol and Consensus-based Standards for the selection of health Measurement Instruments (COSMIN) guidelines, the CAS was translated into traditional Chinese and tested for internal consistency, test-retest reliability, content validity, and construct validity among psychiatric patients in Hong Kong. RESULTS: The CAS was successfully translated into CAS-TC. The CAS-TC version demonstrated good content validity (scale level CVI = 97%), internal consistency (Cronbach's alpha = 0.79), and test-retest reliability (ICC = 0.722 [95% CI, 0.587-0.812]). The CAS-TC showed a two-factor loading for the construct validity, which explained 54% of the total variance. CONCLUSIONS: The CAS-TC is valid and reliable and can be employed to assess constipation among adult psychiatric patients.

Tectoridin Stimulates the Activity of Human Dermal Papilla Cells and Promotes Hair Shaft Elongation in Mouse Vibrissae Hair Follicle Culture.

To search hair growth-promoting herbal extract, a screening platform of having HEK293T fibroblast being transfected with pTOPFLASH DNA construct was developed over a thousand of herbal extracts and phytochemicals were screened. One of the hits was ethanolic extract of Rhizoma Belamcandae, the rhizome of Belamcanda chinensis (L.) DC. Tectoridin, an isoflavone from Rhizoma Belamcandae, was shown to be responsible for this activation of promoter construct, inducing the transcription of pTOPFLASH in the transfected fibroblasts in a dose-dependent manner. The blockage by DKK-1 suggested the action of tectoridin could be mediated by the Wnt receptor. The hair growth-promoting effects of tectoridin were illustrated in human follicular dermal papilla cells and mouse vibrissae organ cultures. In tectoridin-treated dermal papilla cultures, an activation of Wnt signaling was demonstrated by various indicative markers, including TCF/LEF1 transcriptional activity, nuclear translocation of ß-catenin, expressions level of mRNAs encoding axin-related protein, (AXIN2), ß-catenin, lymphoid enhancer-binding factor-1 (LEF-1), insulin-like growth factor 1 (IGF-1) and alkaline phosphatase (ALP). In addition, an increase of hair shaft elongation was observed in cultured mouse vibrissae upon the treatment of tectoridin. Tectoridin, as well as the herbal extract of Rhizoma Belamcandae, possesses hair promoting activity, which deserves further development.

Gut Metabolites Are More Predictive of Disease and Cohoused States than Gut Bacterial Features in a Polycystic Ovary Syndrome-Like Mouse Model.

Polycystic ovary syndrome (PCOS) impacts ∼10% of reproductive-aged women worldwide. In addition to infertility, women with PCOS suffer from metabolic dysregulation which increases their risk of developing type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease. Studies have shown differences in the gut microbiome of women with PCOS compared to controls, a pattern replicated in PCOS-like mouse models. Recently, using a letrozole (LET)-induced mouse model of PCOS, we demonstrated that cohousing was protective against development of metabolic and reproductive phenotypes and showed via 16S amplicon sequencing that this protection correlated with time-dependent shifts in gut bacteria. Here, we applied untargeted metabolomics and shotgun metagenomics approaches to further analyze the longitudinal samples from the cohousing experiment. Analysis of beta diversity found that untargeted metabolites had the strongest correlation to both disease and cohoused states and that shifts in metabolite diversity were detected prior to shifts in bacterial diversity. In addition, log2 fold analyses found numerous metabolite features, particularly bile acids (BAs), to be highly differentiated between placebo and LET, as well as LET cohoused with placebo versus LET. Our results indicate that changes in gut metabolites, particularly BAs, are associated with a PCOS-like phenotype as well as with the protective effect of cohousing. Our results also suggest that transfer of metabolites via coprophagy occurs rapidly and may precipitate changes in bacterial diversity. This study joins a growing body of research linking changes in primary and secondary BAs to host metabolism and gut microbes relevant to the pathology of PCOS. IMPORTANCE Using a combination of untargeted metabolomics and metagenomics, we performed a comparative longitudinal analysis of the feces collected in a cohousing study with a PCOS-like mouse model. Our results showed that gut metabolite composition experienced earlier and more pronounced differentiation in both the disease model and cohoused mice compared with the microbial composition. Notably, statistical and machine learning approaches identified shifts in the relative abundance of primary and secondary BAs, which have been implicated as modifiers of gut microbial growth and diversity. Network correlation analysis showed strong associations between particular BAs and bacterial species, particularly members of Lactobacillus, and that these correlations were time and treatment dependent. Our results provide novel insights into host-microbe relationships related to hyperandrogenism in females and indicate that focused research into small-molecule control of gut microbial diversity and host physiology may provide new therapeutic options for the treatment of PCOS.

A Prospective Randomized Controlled Trial to Compare the Use of Conventional Dark-Ink Tattoo and Ultraviolet-Ink Tattoo for Patients Undergoing Breast Radiation Therapy.

PURPOSE: Permanent tattoo marks used in radiation therapy remain for the duration of treatment and essentially for the rest of the patient's life. This study compared the initial positioning setup errors and body image perception between patients with ultraviolet (UV) and conventional dark ink tattoos. METHODS AND MATERIALS: Thirty-four patients from February 2018 to March 2019, who underwent radiation therapy (RT) to the breast or chest wall for ductal carcinoma in situ or breast cancer were prospectively recruited and randomized (1:1) to receive either conventional dark ink or UV ink tattoos. Each patient received the assigned tattoos during computed tomography (CT) simulation and initial treatment setup shifts were compared. A 9-item body-image survey was administered to all patients at 3 time points: CT simulation, last week of RT, and 6 weeks post-RT. Feedback from CT and treatment staff in terms of setup time and challenges were collated. RESULTS: The median age of the patient cohort was 46 years old. No statistically significant difference was observed between the mean setup errors for the conventional dark ink group (0.11 cm inferior, 0.01 cm left, 0.11 cm posterior) and UV ink group (0.01 cm superior, 0.01 cm right, 0.06 cm posterior; P = NS). Similar responses were observed in the body-image survey between the 2 groups across all time points (P = NS). The majority of the patients (dark ink 82.3% vs UV ink 88.2%) did not feel less sexually attractive as a result of the tattoo at 6 weeks post-RT. At 6 weeks post-RT, patients in both groups were satisfied with the appearance of the tattoo and did not feel cautious about their choice of clothes (82.4% vs 88.2%; P = NS). In addition, 88.6% of staff (n = 35) felt minimum effect of UV ink on the overall setup time, and 94.3% found no difficulty localizing the UV ink tattoos during patient positioning. CONCLUSIONS: No difference in setup accuracy was found using UV ink tattoos, and it could be implemented clinically with minimal effect on the existing workflow. Patients expressed high satisfaction and self-confidence with the use of UV ink tattoos.

Amauroderma rugosum Protects PC12 Cells against 6-OHDA-Induced Neurotoxicity through Antioxidant and Antiapoptotic Effects.

Amauroderma rugosum (AR) is a dietary mushroom in the Ganodermataceae family whose pharmacological activity and medicinal value have rarely been reported. In this study, the antioxidant capacity and neuroprotective effects of AR were investigated. The aqueous extract of AR was confirmed to contain phenolic compounds, polysaccharides, and triterpenes. The results of 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) and total antioxidant capacity assays revealed that AR extract scavenged reactive oxygen species. Moreover, AR extract decreased the cytotoxicity, oxidative stress, mitochondrial dysfunction, and apoptosis of PC12 cells induced by 6-hydroxydopamine (6-OHDA). In addition, 6-OHDA upregulated the expressions of proapoptotic proteins and downregulated the Akt (protein kinase B)/mTOR- (mammalian target of rapamycin-) and MEK (mitogen-activated protein kinase kinase)/ERK- (extracellular signal-regulated kinases-) dependent signaling pathways. These effects of 6-OHDA were abolished or partially reversed by AR extract. Furthermore, the neuroprotective effects of AR in 6-OHDA-treated PC12 cells were significantly abolished by Akt and MEK inhibitor. Thus, AR extract possesses neuroprotective effects, probably through its antioxidant and antiapoptotic effects. These findings suggest the potential application of AR in the prevention or treatment of oxidative stress-related neurodegenerative diseases such as Parkinson's disease.

Automated Computer Vision Assessment of Hypomimia in Parkinson Disease: Proof-of-Principle Pilot Study.

BACKGROUND: Facial expressions require the complex coordination of 43 different facial muscles. Parkinson disease (PD) affects facial musculature leading to "hypomimia" or "masked facies." OBJECTIVE: We aimed to determine whether modern computer vision techniques can be applied to detect masked facies and quantify drug states in PD. METHODS: We trained a convolutional neural network on images extracted from videos of 107 self-identified people with PD, along with 1595 videos of controls, in order to detect PD hypomimia cues. This trained model was applied to clinical interviews of 35 PD patients in their on and off drug motor states, and seven journalist interviews of the actor Alan Alda obtained before and after he was diagnosed with PD. RESULTS: The algorithm achieved a test set area under the receiver operating characteristic curve of 0.71 on 54 subjects to detect PD hypomimia, compared to a value of 0.75 for trained neurologists using the United Parkinson Disease Rating Scale-III Facial Expression score. Additionally, the model accuracy to classify the on and off drug states in the clinical samples was 63% (22/35), in contrast to an accuracy of 46% (16/35) when using clinical rater scores. Finally, each of Alan Alda's seven interviews were successfully classified as occurring before (versus after) his diagnosis, with 100% accuracy (7/7). CONCLUSIONS: This proof-of-principle pilot study demonstrated that computer vision holds promise as a valuable tool for PD hypomimia and for monitoring a patient's motor state in an objective and noninvasive way, particularly given the increasing importance of telemedicine.

Parkinson's disease medication state and severity assessment based on coordination during walking.

Walking is a complex motor function requiring coordination of all body parts. Parkinson's disease (PD) motor signs such as rigidity, bradykinesia, and impaired balance affect movements including walking. Here, we propose a computational method to objectively assess the effects of Parkinson's disease pathology on coordination between trunk, shoulder and limbs during the gait cycle to assess medication state and disease severity. Movements during a scripted walking task were extracted from wearable devices placed at six different body locations in participants with PD and healthy participants. Three-axis accelerometer data from each device was synchronized at the beginning of either left or right steps. Canonical templates of movements were then extracted from each body location. Movements projected on those templates created a reduced dimensionality space, where complex movements are represented as discrete values. These projections enabled us to relate the body coordination in people with PD to disease severity. Our results show that the velocity profile of the right wrist and right foot during right steps correlated with the participant's total score on the gold standard Unified Parkinson's Disease Rating Scale (UPRDS) with an r2 up to 0.46. Left-right symmetry of feet, trunk and wrists also correlated with the total UPDRS score with an r2 up to 0.3. In addition, we demonstrate that binary dopamine replacement therapy medication states (self-reported 'ON' or 'OFF') can be discriminated in PD participants. In conclusion, we showed that during walking, the movement of body parts individually and in coordination with one another changes in predictable ways that vary with disease severity and medication state.

FGF23 signalling and physiology.

Fibroblast growth factor 23 (FGF23) is a phosphotropic hormone that belongs to a subfamily of endocrine FGFs with evolutionarily conserved functions in worms and fruit flies. FAM20C phosphorylates FGF23 post-translationally, targeting it to proteolysis through subtilisin-like proprotein convertase FURIN, resulting in secretion of FGF23 fragments. O-glycosylation of FGF23 through GALNT3 appears to prevent proteolysis, resulting in secretion of biologically active intact FGF23. In the circulation, FGF23 may undergo further processing by plasminogen activators. Crystal structures show that the ectodomain of the cognate FGF23 receptor FGFR1c binds with the ectodomain of the co-receptor alpha-KLOTHO. The KLOTHO-FGFR1c double heterodimer creates a high-affinity binding site for the FGF23 C-terminus. The topology of FGF23 deviates from that of paracrine FGFs, resulting in poor affinity for heparan sulphate, which may explain why FGF23 diffuses freely in the bone matrix to enter the bloodstream following its secretion by cells of osteoblastic lineage. Intact FGF23 signalling by this canonical pathway activates FRS2/RAS/RAF/MEK/ERK1/2. It reduces serum phosphate by inhibiting 1,25-dihydroxyvitamin D synthesis, suppressing intestinal phosphate absorption, and by downregulating the transporters NPT2a and NPT2c, suppressing phosphate reabsorption in the proximal tubules. The physiological role of FGF23 fragments, which may be inhibitory, remains unclear. Pharmacological and genetic activation of canonical FGF23 signalling causes hypophosphatemic disorders, while its inhibition results in hyperphosphatemic disorders. Non-canonical FGF23 signalling through binding and activation of FGFR3/FGFR4/calcineurin/NFAT in an alpha-KLOTHO-independent fashion mainly occurs at extremely elevated circulating FGF23 levels and may contribute to mortality due to cardiovascular disease and left ventricular hypertrophy in chronic kidney disease.

The Impact of Reducing the Number of Wearable Devices on Measuring Gait in Parkinson Disease: Noninterventional Exploratory Study.

BACKGROUND: Measuring free-living gait using wearable devices may offer higher granularity and temporal resolution than the current clinical assessments for patients with Parkinson disease (PD). However, increasing the number of devices worn on the body adds to the patient burden and impacts the compliance. OBJECTIVE: This study aimed to investigate the impact of reducing the number of wearable devices on the ability to assess gait impairments in patients with PD. METHODS: A total of 35 volunteers with PD and 60 healthy volunteers performed a gait task during 2 clinic visits. Participants with PD were assessed in the On and Off medication state using the Movement Disorder Society version of the Unified Parkinson Disease Rating Scale (MDS-UPDRS). Gait features derived from a single lumbar-mounted accelerometer were compared with those derived using 3 and 6 wearable devices for both participants with PD and healthy participants. RESULTS: A comparable performance was observed for predicting the MDS-UPDRS gait score using longitudinal mixed-effects model fit with gait features derived from a single (root mean square error [RMSE]=0.64; R2=0.53), 3 (RMSE=0.64; R2=0.54), and 6 devices (RMSE=0.54; R2=0.65). In addition, MDS-UPDRS gait scores predicted using all 3 models differed significantly between On and Off motor states (single device, P=.004; 3 devices, P=.004; 6 devices, P=.045). CONCLUSIONS: We observed a marginal benefit in using multiple devices for assessing gait impairments in patients with PD when compared with gait features derived using a single lumbar-mounted accelerometer. The wearability burden associated with the use of multiple devices may offset gains in accuracy for monitoring gait under free-living conditions.

Using an unbiased symbolic movement representation to characterize Parkinson's disease states.

Unconstrained human movement can be broken down into a series of stereotyped motifs or 'syllables' in an unsupervised fashion. Sequences of these syllables can be represented by symbols and characterized by a statistical grammar which varies with external situational context and internal neurological state. By first constructing a Markov chain from the transitions between these syllables then calculating the stationary distribution of this chain, we estimate the overall severity of Parkinson's symptoms by capturing the increasingly disorganized transitions between syllables as motor impairment increases. Comparing stationary distributions of movement syllables has several advantages over traditional neurologist administered in-clinic assessments. This technique can be used on unconstrained at-home behavior as well as scripted in-clinic exercises, it avoids differences across human evaluators, and can be used continuously without requiring scripted tasks be performed. We demonstrate the effectiveness of this technique using movement data captured with commercially available wrist worn sensors in 35 participants with Parkinson's disease in-clinic and 25 participants monitored at home.

Slc20a1/Pit1 and Slc20a2/Pit2 are essential for normal skeletal myofiber function and survival.

Low blood phosphate (Pi) reduces muscle function in hypophosphatemic disorders. Which Pi transporters are required and whether hormonal changes due to hypophosphatemia contribute to muscle function is unknown. To address these questions we generated a series of conditional knockout mice lacking one or both house-keeping Pi transporters Pit1 and Pit2 in skeletal muscle (sm), using the postnatally expressed human skeletal actin-cre. Simultaneous conditional deletion of both transporters caused skeletal muscle atrophy, resulting in death by postnatal day P13. smPit1-/-, smPit2-/- and three allele mutants are fertile and have normal body weights, suggesting a high degree of redundance for the two transporters in skeletal muscle. However, these mice show a gene-dose dependent reduction in running activity also seen in another hypophosphatemic model (Hyp mice). In contrast to Hyp mice, grip strength is preserved. Further evaluation of the mechanism shows reduced ERK1/2 activation and stimulation of AMP kinase in skeletal muscle from smPit1-/-; smPit2-/- mice consistent with energy-stress. Similarly, C2C12 myoblasts show a reduced oxygen consumption rate mediated by Pi transport-dependent and ERK1/2-dependent metabolic Pi sensing pathways. In conclusion, we here show that Pit1 and Pit2 are essential for normal myofiber function and survival, insights which may improve management of hypophosphatemic myopathy.

Development of digital biomarkers for resting tremor and bradykinesia using a wrist-worn wearable device.

Objective assessment of Parkinson's disease symptoms during daily life can help improve disease management and accelerate the development of new therapies. However, many current approaches require the use of multiple devices, or performance of prescribed motor activities, which makes them ill-suited for free-living conditions. Furthermore, there is a lack of open methods that have demonstrated both criterion and discriminative validity for continuous objective assessment of motor symptoms in this population. Hence, there is a need for systems that can reduce patient burden by using a minimal sensor setup while continuously capturing clinically meaningful measures of motor symptom severity under free-living conditions. We propose a method that sequentially processes epochs of raw sensor data from a single wrist-worn accelerometer by using heuristic and machine learning models in a hierarchical framework to provide continuous monitoring of tremor and bradykinesia. Results show that sensor derived continuous measures of resting tremor and bradykinesia achieve good to strong agreement with clinical assessment of symptom severity and are able to discriminate between treatment-related changes in motor states.

mHealth and wearable technology should replace motor diaries to track motor fluctuations in Parkinson's disease.

Accurately monitoring motor and non-motor symptoms as well as complications in people with Parkinson's disease (PD) is a major challenge, both during clinical management and when conducting clinical trials investigating new treatments. A variety of strategies have been relied upon including questionnaires, motor diaries, and the serial administration of structured clinical exams like part III of the MDS-UPDRS. To evaluate the potential use of mobile and wearable technologies in clinical trials of new pharmacotherapies targeting PD symptoms, we carried out a project (project BlueSky) encompassing four clinical studies, in which 60 healthy volunteers (aged 23-69; 33 females) and 95 people with PD (aged 42-80; 37 females; years since diagnosis 1-24 years; Hoehn and Yahr 1-3) participated and were monitored in either a laboratory environment, a simulated apartment, or at home and in the community. In this paper, we investigated (i) the utility and reliability of self-reports for describing motor fluctuations; (ii) the agreement between participants and clinical raters on the presence of motor complications; (iii) the ability of video raters to accurately assess motor symptoms, and (iv) the dynamics of tremor, dyskinesia, and bradykinesia as they evolve over the medication cycle. Future papers will explore methods for estimating symptom severity based on sensor data. We found that 38% of participants who were asked to complete an electronic motor diary at home missed ~25% of total possible entries and otherwise made entries with an average delay of >4 h. During clinical evaluations by PD specialists, self-reports of dyskinesia were marked by ~35% false negatives and 15% false positives. Compared with live evaluation, the video evaluation of part III of the MDS-UPDRS significantly underestimated the subtle features of tremor and extremity bradykinesia, suggesting that these aspects of the disease may be underappreciated during remote assessments. On the other hand, live and video raters agreed on aspects of postural instability and gait. Our results highlight the significant opportunity for objective, high-resolution, continuous monitoring afforded by wearable technology to improve upon the monitoring of PD symptoms.

Towards motor evaluation of Parkinson's Disease Patients using wearable inertial sensors.

Parkinson's disease (PD) patients require frequent office visits where they are assessed for health state changes using Unified Parkinson's Disease Rating Scale (UPDRS). Inertial wearable sensor devices present a unique opportunity to supplement these assessments with continuous monitoring. In this work, we analyze kinematic features from sensor devices located on feet, wrists, lumbar and sternum for 35 PD subjects as they performed walk trials in two clinical visits, one for each of their self-reported ON and OFF motor states. Our results show that a few features related to subject's whole-body turns and pronation-supination motor events can accurately infer cardinal features of PD like bradykinesia and posture instability and gait disorder (PIGD). In addition, these features can be measured from only two sensors, one located on the affected wrist and one on the lumbar region, thus potentially reducing patient burden of wearing sensors while supporting continuous monitoring in out of office settings.

Insulin-induced hypoglycaemia suppresses pulsatile luteinising hormone secretion and arcuate Kiss1 cell activation in female mice.

Stress suppresses pulsatile luteinising hormone (LH) secretion in a variety of species, although the mechanism underlying this inhibition of reproductive function remains unclear. Metabolic stress, particularly hypoglycaemia, is a clinically-relevant stress type that is modelled with bolus insulin injection (insulin-induced hypoglycaemia). The present study utilised ovariectomised C57BL/6 mice to test the hypothesis that acute hypoglycaemia suppresses pulsatile LH secretion via central mechanisms. Pulsatile LH secretion was measured in 90-minute sampling periods immediately prior to and following i.p. injection of saline or insulin. The secretion of LH was not altered over time in fed animals or acutely fasted (5 hours) animals following an i.p. saline injection. By contrast, insulin elicited a robust suppression of pulsatile LH secretion in fasted animals, preventing LH pulses in five of six mice. To identify the neuroendocrine site of impairment, a kisspeptin challenge was performed in saline or insulin pre-treated animals in a cross-over design. LH secretion in response to exogenous kisspeptin was not different between animals pre-treated with saline or insulin, indicating normal gonadotrophin-releasing hormone cell and pituitary responses during acute hypoglycaemia. Based on this finding, the effect of insulin-induced hypoglycaemia on arcuate kisspeptin (Kiss1) cell function was determined using c-Fos as a marker of neuronal activation. Insulin caused a significant suppression in the percentage of Kiss1 cells in the arcuate nucleus that contained c-Fos compared to saline-injected controls. Taken together, these data support the hypothesis that insulin-induced hypoglycaemia suppresses pulsatile LH secretion in the female mouse via predominantly central mechanisms, which culminates in the suppression of the arcuate Kiss1 population.