Loss Of Terminals Research Articles

Early locus coeruleus degeneration impairs the longevity of fear memory in APPswe/PS1dE9 mice

AbstractBackgroundThe locus coeruleus (LC), a brainstem noradrenergic nucleus is known to modulate cognitive functions and behaviour. LC is one the first sites of appearance of misfolded tau protein which later develops into neurofibrillary tangles. Hyperphosphorylated tau and amyloid β are best protein correlates of cognitive decline in Alzheimer’s disease (AD). In early onset AD, subtle cognitive deficits develop <25 years before the patients develop dementia. Loss of LC neurons and its innervation has been found to be significantly associated with behavioural deficits observed during prodromal stage of AD. However, the extent and consequences of LC‐noradrenergic system degeneration during early stages of AD pathogenesis are still under investigation.MethodTo address this question, we have performed contextual fear conditioning (cFC) behavioural task to test fear memory in 2‐month‐old APPswe/PS1dE9 (APP/PS1) mice, a transgenic amyloidogenic model of AD. We further investigated the status of LC terminals and the distribution of β‐adrenoceptors (β‐AR) in the hippocampus using dopamine‐β‐hydroxylase (DBH), tyrosine hydroxylase (TH), and β‐AR immunohistochemistry respectively. Finally, we checked if stereotaxic delivery of β‐AR agonist to the hippocampus could rescue the impairments in long‐term fear memory.ResultOur study demonstrates that 2‐month‐old male but not female APP/PS1 mice exhibit impaired long‐term fear memory in cFC task. Immunohistochemical analysis of DBH and TH positive nerve terminals revealed loss of noradrenergic and dopaminergic terminals in male but not female APP/PS1 mice hippocampus. Further, male APP/PS1 mice were found to have low levels of β‐AR in the hippocampus and intra‐hippocampal administration of isoproterenol hydrochloride, a β‐AR agonist, immediately before cFC could restore long‐term contextual fear memory.ConclusionLC‐noradrenergic system degeneration displayed an inherent sex‐specific difference on longevity of fear memory with deficits occurring only in male APP/PS1 mice during early stages of AD.

From Third Space to Transnational: A Study of Alter Identities in Bharati Mukherjee’s Jasmine

The burgeoning presence of the Indian Diaspora across the world has triggered a new consideration of the cultural theories of nation, identity and international affairs. Depicting the process of negotiating the borders, both physical borders of states and countries and the metaphorical borders, between genders generations and cultures, Bharati Mukherjee, an American writer of Indian origin, raises the question of space and identity of the Indian immigrants in the US. An attempt is made to map the journey of the Indian Diaspora from the status of the immigrants to that of the transnational citizens of the world. The scope of this study lies in its treatment of transnational space which is going to redefine the idea of Diaspora as a process of gain, contrary to conventional perspectives that construe immigration and displacement as a condition of terminal loss and dispossession, involving the erasure of history and the dissolution of an “original” culture. Rejecting the binaries of the Western Centre and the Eastern Periphery, the paper invites a post-structural approach to the cultural identity construction of the Indian Diaspora.

BDNF-enriched small extracellular vesicles protect against noise-induced hearing loss in mice

Noise-induced hearing loss (NIHL) is one of the most prevalent acquired sensorineural hearing loss etiologies and is characterized by the loss of cochlear hair cells, synapses, and nerve terminals. Currently, there are no agents available for the treatment of NIHL because drug delivery to the inner ear is greatly limited by the blood–labyrinth barrier. In this study, we used mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) as nanoscale vehicles to deliver brain-derived neurotrophic factor (BDNF) and evaluated their protective effects in a mouse model of NIHL. Following intravenous administration, BDNF-loaded sEVs (BDNF-sEVs) efficiently increased the expression of BDNF protein in the cochlea. Systemic application of sEVs and BDNF-sEVs significantly attenuated noise-induced cochlear hair cell loss and NIHL in CBA/J mice. BDNF-sEVs also alleviated noise-induced loss of inner hair cell ribbon synapses and cochlear nerve terminals. In cochlear explants, sEVs and BDNF-sEVs effectively protected hair cells against H2O2-induced cell loss. Additionally, BDNF-sEVs remarkably ameliorated H2O2-induced oxidative stress, cell apoptosis, and cochlear nerve terminal degeneration. Transcriptomic analysis revealed that many mRNAs and miRNAs were involved in the protective actions of BDNF-sEVs against oxidative stress. Collectively, our findings reveal a novel therapeutic strategy of MSC-sEVs-mediated BDNF delivery for the treatment of NIHL.

Cholinergic centro-cingulate network in Parkinson disease and normal aging.

Decreased cholinergic binding within the recently identified centro-cingulate brain network robustly has been shown to robustly correlate with the severity of cognitive impairment in Parkinson disease (PD). This network with key hubs within the cingulum, operculum and peri-central cortical regions also correlates with elements of parkinsonian motor impairments, including postural instability and gait difficulties, such as falls or freezing. MRI neuroimaging studies have shown that the anterior midcingulate cortex is a key node for cognitive aspects of movement generation, i.e., intentional motor control. Recent evidence also suggests a novel aspect of organization of primary motor cortex, describing "effector" regions for fine movement control intercalated with interlinked "inter-effector" regions devoted to whole-body control. A distinguishing feature of inter-effector regions is tight linkage to the cingular and opercular regions. Such inter-effector regions have been proposed to be part of a greater somato-cognitive action network necessary for integration of goals and movement. Recent evidence also points to vulnerabilities of cholinergic nerve terminals in the centro-cingulate network in older non-PD adults. These features of normal aging underscore that cortical cholinergic terminal losses in age-associated neurodegenerative disorders are likely not exclusively the result of disease-specific etiologies but also related to otherwise normal aging. Practical implications of this overlap are that addressing disease-specific and general aging etiologies involved in neurodegeneration, may be of benefit in age-associated neurodegenerative disorders where significant cholinergic systems degeneration is present.

Fire hazard and risk analysis of large fuel storage tank in IOC terminal

Fires and explosions in large oil storage tanks terminal cause significant loss of property and casualties and are always the concern of the world. To have proper understanding and knowledge about tank fires in terminals a detail study has been done considering various factors like safe separation distance, thermal radiation intensity and deluge water requirement. This paper offers the study of fire hazard especially the radiative heat flux absorbed by adjoining storage tanks. Large storage tanks fire has significant amount of energy release and causes strong thermal radiation to the properties and structures nearby. The thermal radiation intensity has been determined by providing safe separation distance recommended by various standards along with its permissible thermal radiation level for adjoining tanks. The calculated amount of mass flow rate of water required ranges in between 0.09 and 0.23 l/m2s which significantly varies from the recommendations of different code. However, by not ensuring required amount of water as a protective measure to safeguard the target tanks will put its integrity in doubt.

Dermoscopic features of follicular mycosis fungoides of nonscalp areas: Report of 11 cases and literature review

AbstractBackgroundFolliculotropic mycosis fungoides (FMF) is a rare variant of MF that involves hair follicles and requires a more aggressive treatment regime. Significantly, some patients with classic MF can eventually have some degree of follicular involvement.ObjectivesThe aim of this study was to describe the dermoscopic features of FMF in nonscalp areas to facilitate early diagnosis and posttreatment monitoring.MethodsThe clinical and dermoscopic features in 11 FMF patients were analyzed and compared with the reports in the literature.ResultsObliteration of hair follicles, loss of terminal hairs and hair loss were detected in all patients. Follicular accentuation, follicular dilation and broken hairs were found in almost all patients (90.9%). Other common follicular‐based dermoscopic features (<50%) were follicular plugging, perifollicular orange colour, perifollicular erythema and vessels, hyperpigmented halo around the follicle, follicular hyperkeratosis, comedo‐like lesions and perifollicular scales. The most frequent ‘dominant’ dermoscopic features were follicular accentuation with follicular plugging and dilation of follicular opening.ConclusionsIdentification of specific distinguishing dermoscopic patterns of FMF not only could be helpful in classifying MF patients but also could provide prognostic information regarding the disease course and aid in therapeutic decisions. In MF patients, dilation of follicular opening and spiky follicular keratosis are considered the most specific dermoscopic features of follicular involvement since they are uncommon in other conditions.

Educational level and its association with dopamine transporter loss in patients with Parkinson's disease

BackgroundAccording to the cognitive-reserve concept, higher educated dementia patients tolerate more brain pathology than lower educated patients with similar impairment. Here, we examined whether higher education is associated with more severe dopamine terminal loss at the diagnosis of Parkinson's disease (PD). MethodsDopamine transporter (DaT) SPECT information of 352 de novo PD patients and 172 healthy controls (HC) were retrieved from PPMI. Correlation analyses were performed between education years and regional DaT signal (i.e., putamen, caudate, striatum), correcting for UPDRS-III, age, sex and MoCA. Second, using a median split on education (Md = 16 yrs), high and low education groups were determined, which were matched for demographic and/or clinical scores and compared based on regional DaT signals. Finally, moderation analyses were conducted in the PD cohort, assessing the effect of education on the relation between putaminal DaT capacity and UPDRS-III. All analyses were performed across the entire cohorts and separately for three age ranges (sixth, seventh and eighth life decade). ResultsOnly PD patients in their eighth life decade presented a positive association between education and regional dopamine signalling. A significant moderation effect of education on the association between putaminal DaT signal loss and motor symptom severity was observed in this group (B=3.377, t=3.075, p = .003). The remaining analyses did not yield any significant results, neither in the PD nor HC cohort. ConclusionHigher education is not related with greater tolerance against dopamine loss in PD, but may nonetheless assert protective effects at more advanced age.

Neuromuscular junction denervation and terminal Schwann cell loss in the hTDP-43 overexpression mouse model of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with complex aetiology. Despite evidence of neuromuscular junction (NMJ) denervation and 'dying-back' pathology in models of SOD1-dependent ALS, evidence in other genetic forms of ALS is limited by a lack of suitable animal models. TDP-43, a key mediator protein in ALS, is overexpressed in neurons in Thy1-hTDP-43WT mice. We therefore aimed to comprehensively analyse NMJ pathology in this model of ALS. Expression of TDP-43 was assessed via western blotting. Immunohistochemistry techniques, alongside NMJ-morph quantification, were used to analyse motor neuron number, NMJ denervation status and terminal Schwann cell morphology. We present a time course of progressive, region-specific motor neuron pathology in Thy1-hTDP-43WT mice. Thy1-driven hTDP-43 expression increased steadily, correlating with developing hindlimb motor weakness and associated motor neuron loss in the spinal cord with a median survival of 21 days. Pronounced NMJ denervation was observed in hindlimb muscles, mild denervation in cranial muscles but no evidence of denervation in either forelimb or trunk muscles. NMJ pathology was restricted to motor nerve terminals, with denervation following the same time course as motor neuron loss. Terminal Schwann cells were lost from NMJs in hindlimb muscles, directly correlating with denervation status. Thy1-hTDP-43WT mice represent a severe model of ALS, with NMJ pathology/denervation of distal muscles and motor neuron loss, as observed in ALS patients. This model therefore provides an ideal platform to investigate mechanisms of dying-back pathology, as well as NMJ-targeting disease-modifying therapies in ALS.

Patterns of synaptic loss in human amyotrophic lateral sclerosis spinal cord: a clinicopathological study

Amyotrophic Lateral Sclerosis (ALS) is mainly characterized by the degeneration of corticospinal neurons and spinal α-motoneurons; vulnerable cells display prominent pTDP-43 inclusions. Evidence gathered from genetics, murine models, and iPSC-derived neurons point to the early involvement of synapses in the disease course and their crucial role in the pathogenic cascade. However, pathology studies, with specimens from large post-mortem cohorts, mapping the pattern of synaptic disturbances over clinical and neuropathological hallmarks of disease progression, are currently not available. Thus, the appearance and progression of synaptic degeneration in human ALS patients are currently not known, preventing a full validation of the murine and in vitro models. Here, we investigated the loss of synaptophysin-positive terminals in cervical, thoracic, and lumbar spinal cord samples from a retrospective cohort of n = 33 ALS patients and n = 8 healthy controls, and we correlated the loss of synapses against clinicodemographic features and neuropathological ALS stage. We found that, although dorsal and intermediate spinal cord laminae do not lose synapses, ALS patients displayed a substantial but variable loss of synapses in the ventral horn of lumbar and cervical spinal cord. The amount of synaptic loss was predicted by disease duration, by the clinical site of onset, and by the loss of α-motoneurons, although not by the fraction of pTDP-43-immunopositive α-motoneurons. Taken together, our findings validate the synaptic pathology observed in other models and suggest that pathogenic pathways unfolding in the spinal microenvironment are critical to the progressive disassembly of local synaptic connectivity.

Same, same … but different!

This scientific commentary refers to ‘Severe cholinergic terminal loss in newly diagnosed dementia with Lewy bodies’ by Okkels et al. (https://doi.org/10.1093/brain/awad192).

Charge Separation from Triplet Excited States in Nonfullerene Acceptor‐Based Organic Solar Cells

Suppressing charge recombination is pivotal for further improving the power conversion efficiency of organic solar cells (OSCs). The bimolecular recombination of free charge carriers leads to the formation of both singlet and triplet charge transfer (CT) states at a ratio of 1:3 when considering simple spin statistics, meaning that charge recombination via the triplet excited state is the main deactivation channel for OSCs. Although the formation of local triplet excitons through back charge transfer from triplet CT states is thought to be a terminal loss process, it is shown that charge separation from triplet excitons can occur in nonfullerene acceptor (NFA)‐based OSCs. To reveal the triplet exciton dynamics, a triplet sensitizer PtTPBP is doped into an OSC consisting of PM6 and Y6 as an electron donor and acceptor, respectively. Upon photoexcitation of PtTPBP, triplet excitons are formed, which subsequently transfer their energy to Y6, resulting in Y6 triplet excitons formation. Based on transient absorption and external quantum efficiency measurements, clear experimental evidence of charge photogeneration from Y6 triplet excitons at the PM6:Y6 interface is provided. This study highlights the importance of minimizing the energy difference between the singlet and triplet excited states of NFAs to suppress charge recombination.

Increased Free Water in the Putamen in Idiopathic REM Sleep Behavior Disorder.

It has been suggested that the loss of nigrostriatal dopaminergic axon terminals occurs before the loss of dopaminergic neurons in the substantia nigra (SN) in Parkinson's disease (PD). This study aimed to use free-water imaging to evaluate microstructural changes in the dorsoposterior putamen (DPP) of idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) patients, which is considered a prodromal stage of synucleinopathies. Free water values in the DPP, dorsoanterior putamen (DAP), and posterior SN were compared between the healthy controls (n = 48), iRBD (n = 43) and PD (n = 47) patients. In iRBD patients, the relationships between baseline and longitudinal free water values and clinical manifestations or dopamine transporter (DAT) striatal binding ratio (SBR) were analyzed. Free water values were significantly higher in the DPP and posterior substantia nigra (pSN), but not in the DAP, in the iRBD and PD groups than in controls. In iRBD patients, free water values in the DPP were progressively increased and correlated with the progression of clinical manifestations and the striatal DAT SBR. Baseline free water in the DPP was negatively correlated with striatal DAT SBR and hyposmia and positively correlated with motor deficits. This study demonstrates that free water values in the DPP are increased cross-sectionally and longitudinally and associated with clinical manifestations and the function of the dopaminergic system in the prodromal stage of synucleinopathies. Our findings indicate that free-water imaging of the DPP has the potential to be a valid marker of early diagnosis and progression of synucleinopathies. © 2023 International Parkinson and Movement Disorder Society.

Severe cholinergic terminal loss in newly diagnosed dementia with Lewy bodies.

Cholinergic changes play a fundamental role in the natural history of dementia with Lewy bodies and Lewy body disease in general. Despite important achievements in the field of cholinergic research, significant challenges remain. We conducted a study with four main objectives: (i) to examine the integrity of cholinergic terminals in newly diagnosed dementia with Lewy bodies; (ii) to disentangle the cholinergic contribution to dementia by comparing cholinergic changes in Lewy body patients with and without dementia; (iii) to investigate the in vivo relationship between cholinergic terminal loss and atrophy of cholinergic cell clusters in the basal forebrain at different stages of Lewy body disease; and (iv) to test whether any asymmetrical degeneration in cholinergic terminals would correlate with motor dysfunction and hypometabolism. To achieve these objectives, we conducted a comparative cross-sectional study of 25 newly diagnosed dementia with Lewy bodies patients (age 74 ± 5 years, 84% male), 15 healthy control subjects (age 75 ± 6 years, 67% male) and 15 Parkinson's disease patients without dementia (age 70 ± 7 years, 60% male). All participants underwent 18F-fluoroetoxybenzovesamicol PET and high-resolution structural MRI. In addition, we collected clinical 18F-fluorodeoxyglucose PET images. Brain images were normalized to standard space and regional tracer uptake and volumetric indices of basal forebrain degeneration were extracted. Patients with dementia showed spatially distinct reductions in cholinergic terminals across the cerebral cortex, limbic system, thalamus and brainstem. Also, cholinergic terminal binding in cortical and limbic regions correlated quantitatively and spatially with atrophy of the basal forebrain. In contrast, patients without dementia showed decreased cholinergic terminal binding in the cerebral cortex despite preserved basal forebrain volumes. In patients with dementia, cholinergic terminal reductions were most severe in limbic regions and least severe in occipital regions compared to those without dementia. Interhemispheric asymmetry of cholinergic terminals correlated with asymmetry of brain metabolism and lateralized motor function. In conclusion, this study provides robust evidence for severe cholinergic terminal loss in newly diagnosed dementia with Lewy bodies, which correlates with structural imaging measures of cholinergic basal forebrain degeneration. In patients without dementia, our findings suggest that loss of cholinergic terminal function occurs 'before' neuronal cell degeneration. Moreover, the study supports that degeneration of the cholinergic system is important for brain metabolism and may be linked with degeneration in other transmitter systems. Our findings have implications for understanding how cholinergic system pathology contributes to the clinical features of Lewy body disease, changes in brain metabolism and disease progression patterns.

Neural cell state shifts and fate loss in ageing and age-related diseases.

Most age-related neurodegenerative diseases remain incurable owing to an incomplete understanding of the disease mechanisms. Several environmental and genetic factors contribute to disease onset, with human biological ageing being the primary risk factor. In response to acute cellular damage and external stimuli, somatic cells undergo state shifts characterized by temporal changes in their structure and function that increase their resilience, repair cellular damage, and lead to their mobilization to counteract the pathology. This basic cell biological principle also applies to human brain cells, including mature neurons that upregulate developmental features such as cell cycle markers or glycolytic reprogramming in response to stress. Although such temporary state shifts are required to sustain the function and resilience of the young human brain, excessive state shifts in the aged brain might result in terminal fate loss of neurons and glia, characterized by a permanent change in cell identity. Here, we offer a new perspective on the roles of cell states in sustaining health and counteracting disease, and we examine how cellular ageing might set the stage for pathological fate loss and neurodegeneration. A better understanding of neuronal state and fate shifts might provide the means for a controlled manipulation of cell fate to promote brain resilience and repair.

Integrated Fractional-Turn Planar Transformer for MHz and High-Current Applications

In MHz and high current applications, planar transformers face problems such as significant winding loss and limited winding current-carrying capacity, which seriously restrict converter's efficiency and power density improvement. This paper proposes a fractional-turn planar transformer structure and embeds key power devices into the transformer. The proposed method can significantly shorten the winding length, thus reducing winding losses. At the same time, the high integration of the transformer and key power devices can effectively reduce the overall volume of the converter and eliminate terminal losses. The analysis and optimization of the proposed integrated fractional-turn transformer are presented in detail. Finally, a 380V-12V 1kW unregulated LLC is built with the proposed integrated transformer. The full-load efficiency is 97.7%, and the power density is 99W/cm <sup xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">3</sup> , both of which are the highest among the state-of-the-art prototypes with similar specifications.

Differential expression of RET and GDNF family receptor, GFR-α1, between striatum and substantia nigra following nigrostriatal lesion: A case for diminished GDNF-signaling

Although glial cell line-derived neurotrophic factor (GDNF) showed efficacy in preclinical and early clinical studies to alleviate parkinsonian signs in Parkinson's disease (PD), later trials did not meet primary endpoints, giving pause to consider further investigation. While GDNF dose and delivery methods may have contributed to diminished efficacy, one crucial aspect of these clinical studies is that GDNF treatment began ∼8 years after PD diagnosis; a time point representing several years after near 100% depletion of nigrostriatal dopamine markers in striatum and at least 50% in substantia nigra (SN), which represents a time point of initiating GDNF treatment later than reported in some preclinical studies. With nigrostriatal terminal loss exceeding 70% at PD diagnosis, we utilized hemiparkinsonian rats to determine if expression of GDNF family receptor, GFR-α1, and receptor tyrosine kinase, RET, differed between striatum and SN at 1 and 4 weeks following a 6-hydroxydopamine (6-OHDA) hemilesion. Whereas GDNF expression changed minimally, GFR-α1 expression decreased progressively in striatum and in tyrosine hydroxylase positive (TH+) cells in SN, correlating with reduced TH cell number. However, in nigral astrocytes, GFR-α1 expression increased. RET expression decreased maximally in striatum by 1 week, whereas in the SN, a transient bilateral increase occurred, returning to control levels by 4 weeks. Expression of brain-derived neurotrophic factor (BDNF) or its receptor, TrkB, were unchanged throughout lesion progression. Together, these results reveal that differential GFR-α1 and RET expression between the striatum and SN, and cell-specific differences in GFR-α1 expression in SN, occur during nigrostriatal neuron loss. Targeting loss of GDNF receptors thus appears critical to enhance GDNF therapeutic efficacy against nigrostriatal neuron loss. Significance statementAlthough preclinical evidence supports that GDNF provides neuroprotection and improves locomotor function in preclinical studies, there is uncertainty if it can alleviate motor impairment in Parkinson's disease patients. Using the established 6-OHDA hemiparkinsonian rat model, we determined whether expression of its cognate receptors, GFR-α1 and RET, were differentially affected between striatum and substantia nigra in a timeline study. In striatum, there was early and significant loss of RET, but a gradual, progressive loss of GFR-α1. In contrast, RET transiently increased in lesioned substantia nigra, but GFR-α1 progressively decreased only in nigrostriatal neurons and correlated with TH cell loss. Our results indicate that direct availability of GFR-α1 may be a critical element that determines GDNF efficacy following striatal delivery.

Prospective Efficacy and Safety Study of an Innovative Kerascalp Hair Growth Serum in Mild-to-Moderate Alopecia in India: Regrowth Study.

Male and female pattern baldness, commonly known as androgenetic alopecia is the most common type of alopecia, often predetermined genetically, which generally affects the scalp and is characterized by progressive terminal hair loss, known as miniaturization. This study aimed to assess the safety and efficacy of Kerascalp hair serum, a unique combination of esculin, ximenynic acid, and lauric acid, extracted from natural sources in subjects with mild to moderate androgenetic alopecia. An open-label, single-arm clinical study was conducted on healthy males and females aged 18-60 years. Each subject applied the hair serum once daily for 90 days. The efficacy of hair serum was evaluated in terms of the following outcome variables: anagen and telogen ratio (A:T ratio), hair thickness, hair density, hair fall, and hair strength assessment. Subjects were assessed on day 0, day 30, day 60, day 90, and on follow-up day 120. Thirty subjects completed all assessment visits. After using the hair serum for 90 days, statistically significant (p<0.0001) improvement was observed in A:T ratio, hair density, hair thickness, and hair strength; a statistically significant reduction (p<0.0001) in hair fall was also observed. Moreover, improvement in general appearance of hair (in terms of hair volume and density) and scalp (in terms of itchiness, redness, roughness, and dryness) was recorded through dermatological assessment at each treatment visit and at follow-up visit compared to baseline. No adverse event was recorded during the study period, and on follow-up. The results of this clinical study suggest that a 90 days treatment with a phyto-ingredient-based Kerascalp hair serum is safe and effective in significantly improving A:T ratio, hair density, hair thickness, and hair strength, while reducing hair shedding. The improvement in the test parameters persists, even 30 days after stopping the usage of the serum.

New diagnosis of late onset combined immune deficiency in an adult with associated 16p13.3 duplication syndrome

Background16p13 duplication syndrome is a rare chromosomal disorder that manifests with neurocognitive delay/autism, dysmorphic features, and cardiac defects. Severe pneumonia has been documented in patients with this disorder and mostly attributed to abnormal anatomy. To date, no phenotype of immune deficiency has been linked to 16p13 duplication syndrome. Case reportHere we report a case of a 57-year-old female with history of cleft palate, dysmorphia, autism, seizure disorder, uncharacterized myopathic disorder, chronic diarrhea, volvulus, recurrent pneumonias and shingles, and a previous diagnosis of common variable immune deficiency (CVID). Patient presented to our clinic to establish care in the setting of persistent disseminated verruca and recurrent UTIs. She had hypogammaglobulinemia with absent IgA and IgM but normal IgG while on Immunoglobulin infusion (IVIG). Immunophenotyping demonstrated T and NK cell lymphopenia (CD4: 225 cells/µL; CD8: 71 cells/µL; CD56: 29 cells/µL) and absent B cells. Lymphocyte proliferation with antigen and mitogen stimulation was normal. Immune gene panel testing demonstrated three copy number variants (CNV) in CLCN7, HPS3, and SLX4 (all on Chr16) and heterozygous variants of unknown significant (VUS) in FANCI, HPS3, and UNC45A. Chromosomal microarray analysis demonstrated 4.8Mbp copy number gain in the 16p13.3 region (Chr16:383485-5220007) with a terminal 293kbp copy number loss. She remained on IVIG but passed away before additional advanced immune studies could be done. DiscussionThere are few microduplication syndromes that are associated with immune deficiencies including 16p11.2, 19p13, 20p12.2, 22q11.2, and MECP2 duplication. We established a new diagnosis of 16p13.3 duplication syndrome in an adult patient with recurrent cutaneous viral infections, pneumonias, and laboratory features consistent with late onset combined immune deficiency (LOCID). This case report adds to the existing literature on duplication syndromes and associated immune abnormalities.

Voltage Optimization Control and Risk Assessment Technology for High-proportion Distributed Photovoltaic Access to Distribution Network

The high proportion of distributed photovoltaic connected to the distribution network will lead to an increase in terminal voltage and network loss, which will not only generate many adverse effects on the safe and reliable operation of the distribution network but also easily lead to power supply disconnection and power supply interruption accidents caused by voltage out of limit. At present, the voltage control of the distribution network does not fully consider the regulation characteristics of the photovoltaic inverter itself and ignores the impact of different control methods on the distribution network security risk management and control. Therefore, this paper establishes a voltage closed-loop control model for high-proportion distributed photovoltaic access to the distribution network and proposes a real-time active voltage optimization control strategy with the goal of minimizing the deviation of the actual operation state of the distribution network from the scheduling plan. Finally, a typical industrial park is taken as a case for calculation and analysis. The results show that using real-time data to formulate a real-time voltage optimization control strategy can not only ensure the economic operation of each voltage regulating unit in the distribution network but also reduce operational risks. The control method proposed in this paper provides a new idea for improving the voltage control level of distributed photovoltaic access distribution network and fully guarantees the operation reliability of the entire distribution network.

Quantified Striatal Dopaminergic Denervation as Predictor for Motor Outcomes in Parkinson's Disease.

A hallmark of Parkinson's disease (PD) is progressive loss of dopamine terminals in the basal ganglia, with clinical symptoms including motor and non-motor manifestations such as bradykinesia, rigidity, and cognitive impairment. Dopamine transporter single-photon emission computed tomography (DaT-SPECT) can be used to assess dopaminergic denervation by detecting loss of striatal dopamine transporters (DaT). We examined DaT binding scores' (DaTbs) association with motor outcomes in PD and explored its usefulness as a predictor of disease progression. Faster dopaminergic denervation in the basal ganglia was hypothesized to have stronger correlation and predictive value for poor motor outcomes. Data was analyzed from the Parkinson's Progression Markers Initiative. DaTbs in the putamen and caudate nucleus were correlated with Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores for walking and balance difficulties, gait difficulties, and presence of dyskinesias. A predictive model using baseline speed of drop in DaT binding score was performed for each motor outcome. All motor outcomes had mild, significantly negative correlation with DaTbs in the putamen and caudate nucleus, with similar degree of correlation per region. Speed of drop was predictive of only substantial gait difficulties when evaluated in the putamen but not the caudate. These findings suggest that analyzing speed of drop in DaTbs, which occurs early in the motor phase of the disease, may be helpful for predicting clinical outcomes in PD. Longer observation of this cohort may provide further data to investigate DaTbs as a prognostic marker in PD.