Universal Affinity Capture Liquid Chromatography-Mass Spectrometry Assay for Evaluation of Biotransformation of Site-Specific Antibody Drug Conjugates in Preclinical Studies.

Antibody drug conjugates (ADCs) can undergo in vivo biotransformation (e.g., payload metabolism, deconjugation) leading to reduced or complete loss of activity. The location/site of conjugation of payload-linker can have an effect on ADC stability and hence needs to be carefully optimized. Affinity capture LC-MS of intact ADCs or ADC subfragments has been extensively used to evaluate ADC biotransformation. However, the current methods have certain limitations such as the requirement of specific capture reagents, limited mass resolution of low mass change metabolites, low sensitivity, and use of capillary or nanoflow LC-MS. To address these challenges, we developed a generic affinity capture LC-MS assay that can be utilized to evaluate the biotransformation of any site-specific ADC independent of antibody type and site of conjugation (Fab and Fc) in preclinical studies. The method involves a combination of some or all of these steps: (1) "mono capture" or "dual capture" of ADCs from serum with streptavidin magnetic beads coated with a generic biotinylated antihuman capture reagent, (2) "on-bead" digestion with IdeS and/or PNGase F, and (3) reduction of interchain disulfide bonds to generate ∼25 kDa ADC subfragments, which are finally analyzed by LC-HRMS on a TOF mass spectrometer. The advantages of this method are that it can be performed using commercially available generic reagents and requires sample preparation time of less than 7 h. Furthermore, by reducing the size of intact ADC (∼150 kDa) to subfragments (∼25 kDa), the identification of conjugated payload and its metabolites can be achieved with excellent sensitivity and resolution (hydrolysis and other small mass change metabolites). This method was successfully applied to evaluate the in vitro and in vivo biotransformation of ADCs conjugated at different sites (LC, HC-Fab, and HC-Fc) with various classes of payload-linkers.

Corticosteroid-associated lupus pancreatitis: a case series and systematic review of the literature.

BACKGROUND: Acute pancreatitis is an uncommon complication that occurs in 0.85% to 4% of patients with systemic lupus erythematosus (SLE). In some patients, it occurs within days to weeks of starting medium-to-high dose corticosteroids. The authors have used the term 'corticosteroid-associated lupus pancreatitis' for these patients, and they report a case series and perform a systematic review of previously published reports. METHODS: For the purpose of this study, corticosteroid-associated lupus pancreatitis was defined as occurrence of acute pancreatitis in patients with SLE (fulfilling the 1997 ACR), within 3 weeks of starting therapy with medium-to-high dose corticosteroids - either newly initiated or escalated from a lower dose. All patients with SLE admitted in the last 2.5 years in a North Indian university hospital were reviewed, and those with pancreatitis who fulfilled the above criteria were included in the case series. For the systematic review, a PUBMED search using the keywords 'lupus' and 'pancreatitis' was performed, and reports in English were reviewed for an association with corticosteroids. RESULTS: Among 420 admissions of SLE patients, six patients (1.4%) fulfilled criteria for corticosteroid-associated lupus pancreatitis. All were female, with mean age and disease duration of 19.7 ± 3.3 and 3.8 ± 2.5 years respectively. All had active disease and developed acute pancreatitis within 48-72 hours of newly initiating medium-to-high dose corticosteroids (in three patients) or escalating them to medium-high dose (in three patients). After the development of pancreatitis, corticosteroids were continued in all except one patient. In addition, two patients received pulse methylprednisolone, two received pulse cyclophosphamide and one was started on azathioprine. Three patients died during hospitalization, all with severe pancreatitis. On systematic review, among 451 cases of lupus pancreatitis reported, 23 (5%) fulfilled criteria for 'corticosteroid-associated lupus pancreatitis'. A majority of them had pancreatitis within 3 days of starting treatment with medium-to-high dose corticosteroids. The mortality in these patients was 37.5%. CONCLUSION: In a small but substantial proportion of patients with lupus who develop pancreatitis, it occurs within days to weeks of starting medium-to-high dose corticosteroids. Many of these patients continue to receive corticosteroids, and some receive more aggressive immunosuppression. However, they have significant mortality, and further studies are required to identify appropriate treatment in this subgroup of patients.

Uncialamycin as a novel payload for antibody drug conjugate (ADC) based targeted cancer therapy.

Uncialamycin analogs were evaluated as potential cytotoxic agents in an antibody-drug conjugate (ADC) approach to treating human cancer. These analogs were synthesized using Hauser annulations of substituted phthalides as a key step. A highly potent uncialamycin analog 3c with a valine-citrulline dipeptide linker was conjugated to an anti-mesothelin monoclonal antibody (mAb) through lysines to generate a meso-13 conjugate. This conjugate demonstrated subnanomolar potency (IC50 = 0.88 nM, H226 cell line) in in vitro cytotoxicity experiments with good immunological specificity to mesothelin-positive lung cancer cell lines. The potency and mechanism of action of this uncialamycin class of enediyne antitumor antibiotics make them attractive payloads in ADC-based cancer therapy.

Microplastics in the benthic invertebrates from the coastal waters of Kochi, Southeastern Arabian Sea.

This study examined microplastic particles present in the benthic invertebrates Sternaspis scutata, Magelona cinta (deposit feeders) and Tellina sp. (suspension feeder) from the surface sediments of off-Kochi, southwest coast of India. The microplastic particles and thread-like fibres detected in these organisms were identified to be polystyrene by using DXR Raman microscope. Examination of the microplastic particle in Sternaspis scutata by epifluorescent microscopy showed fragmentation marks on the surface suggesting that the microplastic particle was degraded/weathered in nature. The study provides preliminary evidence of the presence of microplastics in benthic fauna from the coastal waters of India. However, further studies are required to understand the sources, distribution, fate and toxicity of the different types of microplastics in benthic invertebrates in order to identify any potential threats to higher trophic level organisms.

Streamlined Total Synthesis of Uncialamycin and Its Application to the Synthesis of Designed Analogues for Biological Investigations.

From the enediyne class of antitumor antibiotics, uncialamycin is among the rarest and most potent, yet one of the structurally simpler, making it attractive for chemical synthesis and potential applications in biology and medicine. In this article we describe a streamlined and practical enantioselective total synthesis of uncialamycin that is amenable to the synthesis of novel analogues and renders the natural product readily available for biological and drug development studies. Starting from hydroxy- or methoxyisatin, the synthesis features a Noyori enantioselective reduction, a Yamaguchi acetylide-pyridinium coupling, a stereoselective acetylide-aldehyde cyclization, and a newly developed annulation reaction that allows efficient coupling of a cyanophthalide and a p-methoxy semiquinone aminal to forge the anthraquinone moiety of the molecule. Overall, the developed streamlined synthesis proceeds in 22 linear steps (14 chromatographic separations) and 11% overall yield. The developed synthetic strategies and technologies were applied to the synthesis of a series of designed uncialamycin analogues equipped with suitable functional groups for conjugation to antibodies and other delivery systems. Biological evaluation of a select number of these analogues led to the identification of compounds with low picomolar potencies against certain cancer cell lines. These compounds and others like them may serve as powerful payloads for the development of antibody drug conjugates (ADCs) intended for personalized targeted cancer therapy.

Sulphoxythiocarbamates modify cysteine residues in HSP90 causing degradation of client proteins and inhibition of cancer cell proliferation.

BACKGROUND: Heat shock protein 90 (HSP90) has a key role in the maintenance of the cellular proteostasis. However, HSP90 is also involved in stabilisation of oncogenic client proteins and facilitates oncogene addiction and cancer cell survival. The development of HSP90 inhibitors for cancer treatment is an area of growing interest as such agents can affect multiple pathways that are linked to all hallmarks of cancer. This study aimed to test the hypothesis that targeting cysteine residues of HSP90 will lead to degradation of client proteins and inhibition of cancer cell proliferation. METHODS: Combining chemical synthesis, biological evaluation, and structure-activity relationship analysis, we identified a new class of HSP90 inhibitors. Click chemistry and protease-mass spectrometry established the sites of modification of the chaperone. RESULTS: The mildly electrophilic sulphoxythiocarbamate alkyne (STCA) selectively targets cysteine residues of HSP90, forming stable thiocarbamate adducts. Without interfering with the ATP-binding ability of the chaperone, STCA destabilises the client proteins RAF1, HER2, CDK1, CHK1, and mutant p53, and decreases proliferation of breast cancer cells. Addition of a phenyl or a tert-butyl group in tandem with the benzyl substituent at nitrogen increased the potency. A new compound, S-4, was identified as the most robust HSP90 inhibitor within a series of 19 derivatives. CONCLUSION: By virtue of their cysteine reactivity, sulphoxythiocarbamates target HSP90, causing destabilisation of its client oncoproteins and inhibiting cell proliferation.

A Detailed Study on using Novel LM 25 Aluminium Alloy Hybrid Metal Matrix Nanocomposite for Nuclear Applications.

AIM: This article describes the use of graphite(Gr) and boron carbide (B4C) as multiple nanoparticle reinforcements in LM25 aluminum alloy. Because boron carbide naturally absorbs neutron radiation, aluminium alloy reinforced with boron carbide metal matrix composite has gained interest in nuclear shielding applications. The primary goal of the endeavor is to create composite materials with high wear resistance, high microhardness, and high ultimate tensile strength for use in nuclear applications. BACKGROUND: Science and Technology have brought a vast change to human life. The human burden has been minimized by the use of innovation in developing new and innovative technologies. To improve the quality of human life, fresh, lightweight, and creative materials are being used, which play a vital role in science and technology and reduce the human workload. Composite materials made of metal are being used because they are lightweight. Neutron absorption, high ultimate strength, high wear resistance, high microhardness, high thermal and electrical conductivity, high vacuum environmental resistance, and low coefficient of thermal expansion under static and dynamic conditions are all demands for the hybrid metal matrix composites utilized in nuclear applications. OBJECTIVE: • Stir casting is used to create the novel LM 25 aluminum alloy/graphite and boron carbide hybrid nanocomposites. • The mechanical properties such as ultimate tensile strength, yield strength, percentage of elongation, microhardness, and wear behavior are calculated. • Three analyses are performed: microstructure, worn surface analysis, and fracture analysis of the tensile specimen. METHOD: • Stir casting process< • Tensile, Hardness, Wear Test • Materials Characterization - FESEM, Optical Microscopy, EDS< Results: The mechanical properties values are 308.76 MPa, 293.51 MPa, 7.8, 169.2 VHN, and 0.01854mm3/m intended for ultimate tensile strength, yield strength, percentage of elongation, microhardness, and wear behavior, respectively. This implies that the synthesized composite may be used in nuclear applications successfully. CONCLUSION: The subsequent explanation was drawn from this investigative work: • The LM 25/B4C/Gr hybrid nanocomposite was successfully manufactured by employing the stir casting technique. For nuclear shielding applications, these composites were prepared with three different weight percentages of nanoparticle reinforcements in 2,4,6% Boron carbide and constant 4 wt.% graphite. • The microhardness values of the three-hybrid nanocomposite fabricated castings were determined to be 143.4VHN, 156.7VHN, and 169.2VHN, respectively. • The hybrid nano composite's microstructure revealed that the underlying LM 25 aluminum alloy matrix's finegrained, evenly dispersed nanoparticles of graphite and boron carbide were present.

• The microtensile test was carried out and it was found that the ultimate tensile strength, yield strength and percentage of elongation values are 281.35MPa, 296.52MPa, 308.76MPa, 269.43, 274.69, 293.51 and 3.4, 5.7, 7.8 respectively.

• Deformation caused the hybrid LM 25/B4C/Gr nanocomposite to fracture in ductile mode. Dimples and cavities are seen in the fracture because of the nanoparticle reinforcements and the matrix's tight connection.

• The wear loss of nanocomposite based on the input parameter applied load, sliding velocity and sliding distance values are 0.02456, 0.02189, 0.01854, 0.02892, 0.02586, 0.02315 and 0.02682, 0.02254, 0.02015 mm3/m, respectively.

• The LM 25 alloy's elemental analysis displays the aluminum alloy phase as the largest peak and the remaining elements as smaller peaks; also, the spectral analysis reveals the presence of boron (B), graphite (C), silicon, and ferrous in the aluminum alloy LM 25.

• Through worn surface FESEM investigation, it was shown that under sliding and high load situations, debris, delamination, and groove develop. Further rupture, fine, and continuous grooves were seen when low stress and sliding circumstances were applied to the LM 25/B4C/Gr and stir cast specimen. This result implies the presence of mild adhesive and delamination wear processes.

Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology.

We have designed and developed novel and selective TLR7 agonists that exhibited potent receptor activity in a cell-based reporter assay. In vitro, these agonists significantly induced secretion of cytokines IL-6, IL-1ß, IL-10, TNFa, IFNa, and IP-10 in human and mouse whole blood. Pharmacokinetic and pharmacodynamic studies in mice showed a significant secretion of IFNα and TNFα cytokines. When combined with aPD1 in a CT-26 tumor model, the lead compound showed strong synergistic antitumor activity with complete tumor regression in 8/10 mice dosed using the intravenous route. Structure-activity relationship studies enabled by structure-based designs of TLR7 agonists are disclosed.

Subunits of the translation initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter.

Leukoencephalopathy with vanishing white matter (VWM) is an inherited brain disease that occurs mainly in children. The course is chronic-progressive with additional episodes of rapid deterioration following febrile infection or minor head trauma. We have identified mutations in EIF2B5 and EIF2B2, encoding the epsilon- and beta-subunits of the translation initiation factor eIF2B and located on chromosomes 3q27 and 14q24, respectively, as causing VWM. We found 16 different mutations in EIF2B5 in 29 patients from 23 families. We also found two distantly related individuals who were homozygous with respect to a missense mutation in EIF2B2, affecting a conserved amino acid. Three other patients also had mutations in EIF2B2. As eIF2B has an essential role in the regulation of translation under different conditions, including stress, this may explain the rapid deterioration of people with VWM under stress. Mutant translation initiation factors have not previously been implicated in disease.

A comparative study of rectal volume variation in patients with prostate cancer: A tertiary care center study.

INTRODUCTION: Every day variations in rectal filling in prostate cancer radiotherapy can significantly alter the delivered dose distribution from what was intended. The goal of this study was to see if the time of treatment delivery affected the rectal filling. METHODS: This is a retrospective study which included 50 patients with localized prostate cancer treated with volumetric modulated arc therapy (VMAT) to the primary and regional lymph nodes. Cone Beam Computed Tomography (CBCT) image-sets were done for all patient's daily setup verification. The radiation therapist contoured the rectum on all CBCT image sets. The rectal volumes delineated on CBCT and the planning CT image sets were compared. The change in rectal volumes between morning and afternoon treatments were calculated and compared. RESULTS: A total of 1000 CBCT image sets were obtained on 50 patients in the morning and afternoon. The percentage variation of the CBCT rectal volumes over the planning CT scan was 16.57% in the AM group and 24.35% in the PM group. CONCLUSION: The percentage change in rectal volume was significantly lesser in AM group compared to PM group and therefore morning treatments may result in dose distribution that is close to the intended dose distribution. IMPLICATIONS FOR PRACTICE: In prostate cancer radiotherapy our study suggests that a simple technique of changing the time of treatment from afternoon to morning can help to reduce the rectal volume.

Export of particulate organic carbon and nitrogen to the northern Indian Ocean by the monsoonal rivers of India.

This study analyses particulate organic carbon (POC) and particulate nitrogen (PN) export from Indian monsoonal rivers to the north Indian Ocean. Indian monsoonal rivers export approximately 1.2 Tg yr-1 (1Tg = 1012 g) of POC and 0.14 Tg yr-1 of PN, with about two-thirds entering the Bay of Bengal (0.8 and 0.1 Tg yr-1, respectively) and the remaining reaches to the Arabian Sea (0.4 and 0.04 Tg yr-1, respectively). Remarkably, just four rivers from northwest India's black soil-dominated regions contribute about half of the total POC and PN exports (0.64 and 0.06 Tg yr-1, respectively). This is due to substantial erosion in these catchments, resulting in suspended matter concentrations averaging 596 ± 252 mg L-1, significantly higher than catchments dominated by red sandy, red loamy and alluvial soils (54 ± 56 mg l-1). In contrast, rivers originating from catchments with heavy precipitation, a tropical wet climate, red loamy soils (with peaty and marshy characteristics), rich tropical wet evergreen and moist deciduous forests, and higher soil organic carbon content yield more POC and PN (1704 ± 383 kgC km-2 yr-1 and 261 ± 56 kgN km-2 yr-1, respectively) than the other rivers of India (951 ± 508 kgC km-2 yr-1 and 120 ± 57 kgN km-2 yr-1, respectively). These findings stress that the export flux and yield of POC and PN from the Indian monsoonal rivers are primarily influenced by the interplay of hydrological, lithological, environmental, and climatic conditions within the catchment, rather than river size. Moreover, this study highlights the significant impact of incorporating POC data from medium-sized rivers worldwide, as it reveals that yield is independent of river size. This calls for a re-evaluation of global POC export fluxes, taking into account hydrological, lithological, environmental, and climatic factors.

Social impairments in Rett syndrome: characteristics and relationship with clinical severity.

BACKGROUND: While behavioural abnormalities are fundamental features of Rett syndrome (RTT), few studies have examined the RTT behavioural phenotype. Most of these reports have focused on autistic features, linked to the early regressive phase of the disorder, and few studies have applied standardised behavioural measures. We used a battery of standardised measures of behaviour and functioning to test the following hypotheses: (1) autistic behaviour is prominent throughout childhood in RTT; (2) autistic features are more salient in individuals with milder presentation; (3) severity of autistic behaviour is associated with a wider range of behavioural problems; and (4) specific MECP2 mutations are linked to more severe autistic behaviour. METHODS: Eighty MECP2 mutation-positive girls with RTT (aged 1.6-14.9 years) were administered: (1) the Screen for Social Interaction (SSI), a measure of autistic behaviour suited for individuals with severe communication and motor impairment; (2) the Rett Syndrome Behaviour Questionnaire (RSBQ), covering a wide range of abnormal behaviours in RTT; (3) the Vineland Adaptive Behavior Scales (VABS); and (4) a modified version of the Rett Syndrome Severity Scale (RSSS). Regression analyses examined the predictive value of age and RSSS on autistic behaviour and other behavioural abnormalities. T-tests further characterised the behavioural phenotype of individual MECP2 mutations. RESULTS: While age had no significant effect on SSI or RSBQ total scores in RTT, VABS Socialization and Composite scores decreased over time. Clinical severity (i.e. RSSS) also increased with age. Surprisingly, SSI performance was not related to either RSSS or VABS Composite scores. Autistic behaviour was weakly linked with the RSBQ Hand behaviour factor scores, but not with the RSBQ Fear/Anxiety factor. Clinical (neurological) severity did not predict RSBQ scores, as evidenced by the analysis of individual MECP2 mutations (e.g. p.R106W, p.R270X and p.R294X). CONCLUSIONS: Our data suggest that in RTT, autistic behaviour persists after the period of regression. It also demonstrated that neurological and behavioural impairments, including autistic features, are relatively independent of one another. Consistent with previous reports of the RTT phenotype, individual MECP2 mutations demonstrate complex associations with autistic features. Evidence of persistent autistic behaviour throughout childhood, and of a link between hand function and social skills, has important implications not only for research on the RTT behavioural phenotype, but also for the clinical management of the disorder.

Characterization of plastic debris from surface waters of the eastern Arabian Sea-Indian Ocean.

The quantity of floating plastic debris (FPD) is continuously being increased in the oceans. To assess their size, structure, and composition along the eastern Arabian Sea (EAS), FPD samples were collected by using a surface plankton net. The microplastic size fraction (0.5-5 mm) was the most prevalent accounting for >50% of the total, followed by mesoplastics (5-25 mm; ~40%) and macroplastics (>25 mm; ~10%). The collected FPDs were categorized into five different types and eight colours. Attenuated Total Reflectance-Fourier Transform Infrared Spectrometry (ATR-FTIR) analysis of the plastics revealed that polypropylene, polyethylene, and nylon were the most dominant polymers, and these comprised mostly of fibre/fishing line. The abundance of FPD in the EAS (0.013 ± 0.012 no.s/m3) was found to be very low compared to elsewhere. The prevalent microplastics presence in the oceans might have occurred mainly by the degradation of larger items. It increases bioavailability, and hence, is a risk to marine ecosystems.

DNA-Model-Based Design and Execution of Some Fused Benzodiazepine Hybrid Payloads for Antibody-Drug Conjugate Modality.

A new series with the tetrahydroisoquinoline-fused benzodiazepine (TBD) ring system combined with the surrogates of (1-methyl-1H-pyrrol-3-yl)benzene ("MPB") payloads were designed and executed for conjugation with a monoclonal antibody for anticancer therapeutics. DNA models helped in rationally identifying modifications of the "MPB" binding component and guided structure-activity relationship generation. This hybrid series of payloads exhibited excellent in vitro activity when tested against a panel of various cancer cell lines. One of the payloads was appended with a lysosome-cleavable peptide linker and conjugated with an anti-mesothelin antibody via a site-specific conjugation method mediated by the enzyme bacterial transglutaminase (BTGase). Antibody-drug conjugate (ADC) 50 demonstrated good plasma stability and lysosomal cleavage. A single intravenous dose of ADC 50 (5 or 10 nmol/kg) showed robust efficacy in an N87 gastric cancer xenograft model.

The effect of aloe vera and tea tree oil mouthwashes on the oral health of school children.

PURPOSE: To evaluate the effect of two herbal mouthwashes containing aloe vera and tea tree oil, on the oral health of school children. METHODS: A double-blinded, placebo-controlled prospective interventional study was conducted in school children aged 8-14 years. The study participants were divided into four groups depending upon the mouthwash used: Group 1 (aloe vera), Group 2 (chlorhexidine), Group 3 (tea tree oil) and Group 4 (placebo). The variables studied included plaque index, gingival index and salivary Streptococcus mutans counts, which were recorded at baseline, 4 weeks after supervised mouth rinse and after 2 weeks of stopping the mouth rinse. RESULTS: A total of 89 boys and 63 girls were included. A statistically significant decrease in all variables was noted after the use of both the herbal preparations at the end of 4 weeks which was maintained after the 2-week washout period (p < 0.001). The difference in variables between groups using aloe vera, Tea tree oil and chlorhexidine, was not statistically significant. CONCLUSION: The use of aloe vera and tea tree oil mouthwashes can decrease plaque, gingivitis and S. mutans in the oral cavity in children. The activity of these two agents is comparable to that of chlorhexidine.

Total Synthesis of Meayamycin and O-Acyl Analogues.

A short, scalable total synthesis of meayamycin is described by an approach that entails a longest linear sequence of 12 steps (22 steps overall) from commercially available chiral pool materials (ethyl l-lactate, BocNH-Thr-OH, and d-ribose) and introduces the most straightforward preparation of the right-hand subunit detailed to date. The use of the approach in the divergent synthesis of a representative series of O-acyl analogues is exemplified.

Chemical Modification of Linkers Provides Stable Linker-Payloads for the Generation of Antibody-Drug Conjugates.

Stability of antibody-drug conjugates (ADCs) in mouse serum is one of the critical requirements for the evaluation of ADCs in mouse tumor models. Described herein is a strategy to address the mouse serum instability of uncialamycin linker-payloads through various chemical approaches that involve modification of different parts of the linker and payload. This effort ultimately led to the identification of a m-amide p-aminobenzyl carbamate (MA-PABC) group that resulted in linkers with dramatic improvement of mouse serum stability without affecting the desired proteolytic cleavage.

Design, Synthesis, and Structure-Activity Relationships of Novel Tetrahydroisoquinolino Benzodiazepine Dimer Antitumor Agents and Their Application in Antibody-Drug Conjugates.

A series of tetrahydroisoquinoline-based benzodiazepine dimers were synthesized and tested for in vitro cytotoxicity against a panel of cancer cell lines. Structure-activity relationship investigation of various spacers guided by molecular modeling studies helped to identify compounds with picomolar activity. Payload 17 was conjugated to anti-mesothelin and anti-fucosylated monosialotetrahexosylganglioside (FucGM1) antibodies using lysosome-cleavable valine-citrulline dipeptide linkers via heterogeneous lysine conjugation and bacterial transglutaminase-mediated site-specific conjugation. In vitro, these antibody drug conjugates (ADCs) exhibited significant cytotoxic and target-mediated selectivity on human cancer cell lines. The pharmacokinetics and efficacy of these ADCs were further evaluated in gastric and lung cancer xenograft models in mice. Consistent pharmacokinetic profiles, high target specificity, and robust antitumor activity were observed in these models after a single dose of the ADC-46 (0.02 µmol/kg).

Two cases with progressive cystic leukoencephalopathy.

Leukoencephalopathies with cystic changes in the white matter on magnetic resonance imaging are aetiologically heterogeneous neurological disorders seen in children. A group of leukoencephalopathies characterised by white matter lesions progressing to multifocal cystic degeneration has been reported in various disorders, including mitochondrial enzyme deficiencies, leukodystrophies, and infectious processes. We report two patients with leukoencephalopathy showing progressive cystic changes on serial MRI, and magnetic resonance spectroscopy resembling progressive cavitating leukoencephalopathy.

Increased Functional Connectivity After Listening to Favored Music in Adults With Alzheimer Dementia.

BACKGROUND: Personalized music programs have been proposed as an adjunct therapy for patients with Alzheimer disease related dementia, and multicenter trials have now demonstrated improvements in agitation, anxiety, and behavioral symptoms. Underlying neurophysiological mechanisms for these effects remain unclear. METHODS: We examined 17 individuals with a clinical diagnosis of Alzheimer disease related dementia using functional MRI following a training period in a personalized music listening program. RESULTS: We find that participants listening to preferred music show specific activation of the supplementary motor area, a region that has been associated with memory for familiar music that is typically spared in early Alzheimer disease. We also find widespread increases in functional connectivity in corticocortical and corticocerebellar networks following presentation of preferred musical stimuli, suggesting a transient effect on brain function. CONCLUSIONS: Findings support a mechanism whereby attentional network activation in the brain's salience network may lead to improvements in brain network synchronization.