Combination CPAP and bilateral hypoglossal nerve stimulation for obstructive sleep apnea in Treacher Collins syndrome: first case report.

We report the first case of bilateral hypoglossal nerve stimulator implantation in a patient with Treacher Collins syndrome and very severe obstructive sleep apnea, who was initially intolerant of continuous positive airway pressure (CPAP) treatment. Novel bilateral hypoglossal nerve stimulation in combination with CPAP allowed near obliteration of snoring, improved sleep quality, and ability to maintain the CPAP mask in position in the setting of craniofacial changes associated with this condition. CITATION: Wong ACL, Jones A, Stone A, MacKay SG. Combination CPAP and bilateral hypoglossal nerve stimulation for obstructive sleep apnea in Treacher Collins syndrome: first case report. J Clin Sleep Med. 2023;19(1):197-199.

Prevalence of the interthalamic adhesion in the human brain: a review of literature.

The interthalamic adhesion (IA) is a midline structure connecting the two thalami. Though it has been studied for centuries its exact function remains elusive. Early studies had noted its peculiar absence even among some healthy individuals. Population studies have investigated the differences in prevalence of IA in pathologic conditions and healthy controls. However, there is a general lack of consensus on IA prevalence in the healthy population. Understanding the true prevalence is critical in providing context for future studies, as well as uncovering further clues regarding IA's function. We systematically reviewed the existing literature to evaluate the prevalence of IA. The average prevalence among reviewed studies was higher than previously reported, at 87.3%. Studies utilizing magnetic resonance imaging rather than cadaveric specimens reported higher rates of IA prevalence. A higher prevalence among females was noted throughout the literature that persisted regardless of acquisition modality utilized.

Vitamin C Bioequivalence from Gummy and Caplet Sources in Healthy Adults: A Randomized-Controlled Trial.

Background: The efficacy of Vitamin C (L-ascorbic acid) supplementation can be assessed by uptake into the blood and retention in leukocytes. Vitafusion® Power C gummy is an alternative vitamin C source which may exhibit similar bioavailability to comparator caplets.Objective: The objective of this study was to evaluate the bioequivalence of vitamin C from a vitafusion® Power C gummy formulation and a comparator caplet in healthy adults.Methods: Thirty healthy men and women, 34.0 ± 11.4 years of age and Body Mass Index (BMI) 24.5 ± 3.6 kg/m2 completed the randomized examiner-blind, comparator controlled, cross-over trial with two sequences: gummy (1000 mg) to caplet (1000 mg) or caplet to gummy. Intake of foods fortified with Vitamin C was restricted 7 days prior to each dosing. Blood samples were collected pre-dose and at 0.5, 1, 2, 3, 4, 5, 6, 8, 10, 12 and 24 h post-dose for plasma and leukocytes; and urine was collected pre-dose and between 0-2, 2-4, 4-8, 8-12 and 12-24 h post-dose for L-ascorbic acid analysis.Results: Vitafusion® Power C gummy and comparator caplet demonstrated similar plasma absorption profiles as there were no significant differences in plasma L-ascorbic acid total Area Under the Curve (AUC)0-24h, and Tmax between gummy and caplet. The caplet did elicit a significantly higher Cmax than the gummy (p < 0.05), however, the difference was numerically small. Leukocyte L-ascorbic acid total AUC0-24h and Cmax were not significantly different between gummy and caplet, however Tmax of the gummy group was significantly longer (p = 0.012). Urinary L-ascorbic acid levels were also not significantly different between gummy and caplet. There were no serious adverse events and safety parameters remained within normal clinical range for both products.Conclusion: Vitafusion® Power C gummy exhibited similar Vitamin C absorption and bioavailability to a comparator caplet in healthy adults and were considered bioequivalent.

Online classification of imagined speech using functional near-infrared spectroscopy signals.

OBJECTIVE: Most brain-computer interfaces (BCIs) based on functional near-infrared spectroscopy (fNIRS) require that users perform mental tasks such as motor imagery, mental arithmetic, or music imagery to convey a message or to answer simple yes or no questions. These cognitive tasks usually have no direct association with the communicative intent, which makes them difficult for users to perform. APPROACH: In this paper, a 3-class intuitive BCI is presented which enables users to directly answer yes or no questions by covertly rehearsing the word 'yes' or 'no' for 15 s. The BCI also admits an equivalent duration of unconstrained rest which constitutes the third discernable task. Twelve participants each completed one offline block and six online blocks over the course of two sessions. The mean value of the change in oxygenated hemoglobin concentration during a trial was calculated for each channel and used to train a regularized linear discriminant analysis (RLDA) classifier. MAIN RESULTS: By the final online block, nine out of 12 participants were performing above chance (p < 0.001 using the binomial cumulative distribution), with a 3-class accuracy of 83.8% ± 9.4%. Even when considering all participants, the average online 3-class accuracy over the last three blocks was 64.1 % ± 20.6%, with only three participants scoring below chance (p < 0.001). For most participants, channels in the left temporal and temporoparietal cortex provided the most discriminative information. SIGNIFICANCE: To our knowledge, this is the first report of an online 3-class imagined speech BCI. Our findings suggest that imagined speech can be used as a reliable activation task for selected users for development of more intuitive BCIs for communication.

Risk factors and clinical course of hungry bone syndrome after total parathyroidectomy in dialysis patients with secondary hyperparathyroidism.

BACKGROUND: Hungry bone syndrome (HBS) is an important postoperative complication after parathyroidectomy for severe secondary hyperparathyroidism (SHPT). There is, however, little data in the literature on its detailed clinical course, and the associated risk factors remain controversial. METHODS: We did a single-center retrospective study on 62 consecutive dialysis patients who underwent total parathyroidectomy for SHPT to examine the risk factors, clinical course and outcome. Data on demographic characteristics, perioperative laboratory parameters including serum calcium, phosphate, alkaline phosphatase (ALP) and parathyroid hormone (PTH), drug treatment for SHPT and operative details of parathyroidectomy were collected. RESULTS: Seventeen (27.4%) patients developed severe postoperative hypocalcemia with HBS. The serum calcium dropped progressively while serum ALP rose after operation until 2 weeks later when serum calcium reached the trough and serum ALP peaked. Serum phosphate also fell but stabilized between 4 and 14 days. The total postoperative calcium and vitamin D supplementation was significantly larger, and hospital stay was significantly longer in the group with HBS as compared with those without HBS. Young age, high body weight, high preoperative ALP level, and low preoperative calcium level independently predicted the development of HBS while preoperative PTH and use of cinacalcet or paricalcitol did not. CONCLUSION: HBS was common after total parathyroidectomy in patients with SHPT, and it is important to closely monitor the postoperative serum calcium, phosphate and ALP levels in the following 2 weeks, especially for those at risk. The implications of our findings on perioperative management are discussed.

Effect of Local Anesthetic Concentration (0.2% vs 0.1% Ropivacaine) on Pulmonary Function, and Analgesia After Ultrasound-Guided Interscalene Brachial Plexus Block: A Randomized Controlled Study.

OBJECTIVE: This study aims to assess diaphragmatic excursion and measure pulmonary functions as measures of the degree to which the phrenic nerve is blocked after ISB with two different concentrations of ropivacaine: 0.2% and 0.1%. DESIGN: Randomized, double-blinded study. SETTING AND PATIENTS: Ambulatory surgical facility. SUBJECTS: Fifty patients undergoing shoulder arthroscopy for rotator cuff repair. METHODS: Patients were randomized to receive ultrasound-guided ISB with 20 mL of either 0.2% or 0.1% ropivacaine. Diaphragmatic excursion was measured using M-mode ultrasound. Pulmonary functions were assessed by portable spirometer. Additional outcome data included oxygen saturation in post-anesthesia care unit (PACU), pain scores, quality of recovery scores (QOR), and opioid consumption over 72 hour period after surgery. RESULTS: Forced vital capacity (FVC) was significantly reduced 30 minutes after block placement and in PACU in the 0.2% group when compared with the 0.1% group (P = 0.04, P = 0.03, respectively). Forced expiratory volume (FEV1) was also significantly decreased in the 0.2% group in PACU when compared with the 0.1% group (P = 0.04). There were no significant differences in pain scores, length of stay, and total opioid consumption in PACU. Patients who received 0.2% ropivacaine had a longer block duration (18 vs 11.9 hours, P = 0.04) and used less opioid in the 72 hours after surgery (55 mg vs 102 mg codeine equivalents, P = 0.02), when they were compared to their counterparts who received 0.1% for their block. CONCLUSION: 0.1% ropivacaine may impair pulmonary function less than 0.2% ropivacaine. The clinical significance of these differences needs to be further studied.

Endoscopic and non-endoscopic approaches for the management of radiation-induced rectal bleeding.

Pelvic radiation is a commonly utilized treatment for malignancy of the genitourinary and lower gastrointestinal tract. Radiation proctitis and the resultant clinical picture varies from asymptomatic to potentially life threatening. Similarly, treatment options also vary greatly, from medical therapy to surgical intervention. Commonly utilized medical therapy includes sucralfate enemas, antibiotics, 5-aminosalicylic acid derivatives, probiotics, antioxidants, short-chain fatty acids, formalin instillation and fractionated hyperbaric oxygen. More invasive treatments include endoscopic-based, focally ablative interventions such as dilation, heater and bipolar cautery, neodymium/yttrium aluminum garnet argon laser, radiofrequency ablation or argon plasma coagulation. Despite its relatively common frequency, there is a dearth of existing literature reporting head-to-head comparisons of the various treatment options via a randomized controlled approach. The purpose of our review was to present the reader a consolidation of the existing evidence-based literature with the goal of highlighting the comparative effectiveness and risks of the various treatment approaches. Finally, we outline a pragmatic approach to the treatment of radiation proctitis. In light of the lack of randomized data, our goal is to pursue as least invasive an approach as possible, with escalation of care tailored to the severity of the patient's symptoms. For those cases that are clinically asymptomatic or only mildly symptomatic, observation or medical management can be considered. Once a patient fails such management or symptoms become more severe, invasive procedures such as endoscopically based focal ablation or surgical intervention can be considered. Although not all recommendations are supported by level I evidence, reported case series and single-institutional studies in the literature suggest that successful treatment with cessation of symptoms can be obtained in the majority of cases.

Partitioning and correlating subgroup characteristics from Aligned Pattern Clusters.

MOTIVATION: Evolutionarily conserved amino acids within proteins characterize functional or structural regions. Conversely, less conserved amino acids within these regions are generally areas of evolutionary divergence. A priori knowledge of biological function and species can help interpret the amino acid differences between sequences. However, this information is often erroneous or unavailable, hampering discovery with supervised algorithms. Also, most of the current unsupervised methods depend on full sequence similarity, which become inaccurate when proteins diverge (e.g. inversions, deletions, insertions). Due to these and other shortcomings, we developed a novel unsupervised algorithm which discovers highly conserved regions and uses two types of information measures: (i) data measures computed from input sequences; and (ii) class measures computed using a priori class groupings in order to reveal subgroups (i.e. classes) or functional characteristics. RESULTS: Using known and putative sequences of two proteins belonging to a relatively uncharacterized protein family we were able to group evolutionarily related sequences and identify conserved regions, which are strong homologous association patterns called Aligned Pattern Clusters, within individual proteins and across the members of this family. An initial synthetic demonstration and in silico results reveal that (i) the data measures are unbiased and (ii) our class measures can accurately rank the quality of the evolutionarily relevant groupings. Furthermore, combining our data and class measures allowed us to interpret the results by inferring regions of biological importance within the binding domain of these proteins. Compared to popular supervised methods, our algorithm has a superior runtime and comparable accuracy. AVAILABILITY AND IMPLEMENTATION: The dataset and results are available at www.pami.uwaterloo.ca/∼ealee/files/classification2015 CONTACT: akcwong@uwaterloo.ca SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Nonclinical evaluation of CNS-administered TPP1 enzyme replacement in canine CLN2 neuronal ceroid lipofuscinosis.

The CLN2 form of neuronal ceroid lipofuscinosis, a type of Batten disease, is a lysosomal storage disorder caused by a deficiency of the enzyme tripeptidyl peptidase-1 (TPP1). Patients exhibit progressive neurodegeneration and loss of motor, cognitive, and visual functions, leading to death by the early teenage years. TPP1-null Dachshunds recapitulate human CLN2 disease. To characterize the safety and pharmacology of recombinant human (rh) TPP1 administration to the cerebrospinal fluid (CSF) as a potential enzyme replacement therapy (ERT) for CLN2 disease, TPP1-null and wild-type (WT) Dachshunds were given repeated intracerebroventricular (ICV) infusions and the pharmacokinetic (PK) profile, central nervous system (CNS) distribution, and safety were evaluated. TPP1-null animals and WT controls received 4 or 16mg of rhTPP1 or artificial cerebrospinal fluid (aCSF) vehicle every other week. Elevated CSF TPP1 concentrations were observed for 2-3 days after the first ICV infusion and were approximately 1000-fold higher than plasma levels at the same time points. Anti-rhTPP1 antibodies were detected in CSF and plasma after repeat rhTPP1 administration, with titers generally higher in TPP1-null than in WT animals. Widespread brain distribution of rhTPP1 was observed after chronic administration. Expected histological changes were present due to the CNS delivery catheters and were similar in rhTPP1 and vehicle-treated animals, regardless of genotype. Neuropathological evaluation demonstrated the clearance of lysosomal storage, preservation of neuronal morphology, and reduction in brain inflammation with treatment. This study demonstrates the favorable safety and pharmacology profile of rhTPP1 ERT administered directly to the CNS and supports clinical evaluation in patients with CLN2 disease.

Discovering co-occurring patterns and their biological significance in protein families.

BACKGROUND: The large influx of biological sequences poses the importance of identifying and correlating conserved regions in homologous sequences to acquire valuable biological knowledge. These conserved regions contain statistically significant residue associations as sequence patterns. Thus, patterns from two conserved regions co-occurring frequently on the same sequences are inferred to have joint functionality. A method for finding conserved regions in protein families with frequent co-occurrence patterns is proposed. The biological significance of the discovered clusters of conserved regions with co-occurrences patterns can be validated by their three-dimensional closeness of amino acids and the biological functionality found in those regions as supported by published work. METHODS: Using existing algorithms, we discovered statistically significant amino acid associations as sequence patterns. We then aligned and clustered them into Aligned Pattern Clusters (APCs) corresponding to conserved regions with amino acid conservation and variation. When one APC frequently co-occurred with another APC, the two APCs have high co-occurrence. We then clustered APCs with high co-occurrence into what we refer to as Co-occurrence APC Clusters (Co-occurrence Clusters). RESULTS: Our results show that for Co-occurrence Clusters, the three-dimensional distance between their amino acids is closer than average amino acid distances. For the Co-occurrence Clusters of the ubiquitin and the cytochrome c families, we observed biological significance among the residing amino acids of the APCs within the same cluster. In ubiquitin, the residues are responsible for ubiquitination as well as conventional and unconventional ubiquitin-bindings. In cytochrome c, amino acids in the first co-occurrence cluster contribute to binding of other proteins in the electron transport chain, and amino acids in the second co-occurrence cluster contribute to the stability of the axial heme ligand. CONCLUSIONS: Thus, our co-occurrence clustering algorithm can efficiently find and rank conserved regions that contain patterns that frequently co-occurring on the same proteins. Co-occurring patterns are biologically significant due to their three-dimensional closeness and other evidences reported in literature. These results play an important role in drug discovery as biologists can quickly identify the target for drugs to conduct detailed preclinical studies.

Extensive Ace2 duplication and multiple mutations on Ace1 and Ace2 are related with high level of organophosphates resistance in Aphis gossypii.

Aphis gossypii (Glover) has been found to possess multiple mutations in the acetylcholinesterase (AChE) gene (Ace) that might involve target site insensitivity. In vitro functional expression of AChEs reveals that the resistant Ace1 (Ace1R) and Ace2 (Ace2R) were significantly less inhibited by eserine, omethoate, and malaoxon than the susceptible Ace1 (Ace1S) and Ace2 (Ace2S). Furthermore, in both the mutant and susceptible AChEs, Ace2 was significantly less sensitive to eserine, omethoate, and malaoxon than Ace1. These results suggested that both the mutant Ace1 and Ace2 were responsible for omethoate resistance, while the mutant Ace2 played a major role in insecticide resistance. The DNA copy number and transcription level of Ace2 were 1.52- and 1.88-fold higher in the ORR strain than in the OSS strain. Furthermore, the DNA copy number and transcription level of Ace2 were significantly higher than that of Ace1 in either OSS or ORR strains, demonstrating the involvement of Ace2 gene duplication in resistance. Thus, the authors conclude that omethoate resistance in cotton aphids appears to have evolved through a combination of multiple mutations and extensive Ace2R gene duplication.

Single domain antibody against carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) inhibits proliferation, migration, invasion and angiogenesis of pancreatic cancer cells.

Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) is over-expressed in pancreatic cancer cells, and it is associated with the progression of pancreatic cancer. We tested a single domain antibody (sdAb) targeting CEACAM6, 2A3, which was isolated previously from a llama immune library, and an Fc conjugated version of this sdAb, to determine how they affect the pancreatic cancer cell line BxPC3. We also compared the effects of the antibodies to gemcitabine. Gemcitabine and 2A3 slowed down cancer cell proliferation. However, only 2A3 retarded cancer cell invasion, angiogenesis within the cancer mass and BxPC3 cell MMP-9 activity, three features important for tumour growth and metastasis. The IC50s for 2A3, 2A3-Fc and gemcitabine were determined as 6.5µM, 8µM and 12nM, respectively. While the 2A3 antibody inhibited MMP-9 activity by 33% compared to non-treated control cells, gemcitabine failed to inhibit MMP-9 activity. Moreover, 2A3 and 2A3-Fc inhibited invasion of BxPC3 by 73% compared to non-treated cells. When conditioned media that were produced using 2A3- or 2A3-Fc-treated BxPC3 cells were used in a capillary formation assay, the capillary length was reduced by 21% and 49%, respectively. Therefore 2A3 is an ideal candidate for treating tumours that over-express CEACAM6.

Toward an understanding of changes in diversity associated with fecal microbiome transplantation based on 16S rRNA gene deep sequencing.

Fecal microbiome transplantation by low-volume enema is an effective, safe, and inexpensive alternative to antibiotic therapy for patients with chronic relapsing Clostridium difficile infection (CDI). We explored the microbial diversity of pre- and posttransplant stool specimens from CDI patients (n = 6) using deep sequencing of the 16S rRNA gene. While interindividual variability in microbiota change occurs with fecal transplantation and vancomycin exposure, in this pilot study we note that clinical cure of CDI is associated with an increase in diversity and richness. Genus- and species-level analysis may reveal a cocktail of microorganisms or products thereof that will ultimately be used as a probiotic to treat CDI. IMPORTANCE Antibiotic-associated diarrhea (AAD) due to Clostridium difficile is a widespread phenomenon in hospitals today. Despite the use of antibiotics, up to 30% of patients are unable to clear the infection and suffer recurrent bouts of diarrheal disease. As a result, clinicians have resorted to fecal microbiome transplantation (FT). Donor stool for this type of therapy is typically obtained from a spouse or close relative and thoroughly tested for various pathogenic microorganisms prior to infusion. Anecdotal reports suggest a very high success rate of FT in patients who fail antibiotic treatment (>90%). We used deep-sequencing technology to explore the human microbial diversity in patients with Clostridium difficile infection (CDI) disease after FT. Genus- and species-level analysis revealed a cocktail of microorganisms in the Bacteroidetes and Firmicutes phyla that may ultimately be used as a probiotic to treat CDI.

Early glial activation, synaptic changes and axonal pathology in the thalamocortical system of Niemann-Pick type C1 mice.

Niemann-Pick disease type C (NPC) is an inherited lysosomal storage disease characterised by accumulation of cholesterol and glycosphingolipids. NPC patients suffer a progressive neurodegenerative phenotype presenting with motor dysfunction, mental retardation and cognitive decline. To examine the onset and progression of neuropathological insults in NPC we have systematically examined the CNS of a mouse model of NPC1 (Npc1(-/-) mice) at different stages of the disease course. This revealed a specific spatial and temporal pattern of neuropathology in Npc1(-/-) mice, highlighting that sensory thalamic pathways are particularly vulnerable to loss of NPC1 resulting in neurodegeneration in Npc1(-/-) mice. Examination of markers of astrocytosis and microglial activation revealed a particularly pronounced reactive gliosis in the thalamus early in the disease, which subsequently also occurred in interconnected cortical laminae at later ages. Our examination of the precise staging of events demonstrate that the relationship between glia and neurons varies between brain regions in Npc1(-/-) mice, suggesting that the cues causing glial reactivity may differ between brain regions. In addition, aggregations of pre-synaptic markers are apparent in white matter tracts and the thalamus and are likely to be formed within axonal spheroids. Our data provide a new perspective, revealing a number of events that occur prior to and alongside neuron loss and highlighting that these occur in a pathway dependent manner.

Molecular correlates of axonal and synaptic pathology in mouse models of Batten disease.

Neuronal ceroid lipofuscinoses (NCLs; Batten disease) are collectively the most frequent autosomal-recessive neurodegenerative disease of childhood, but the underlying cellular and molecular mechanisms remain unclear. Several lines of evidence have highlighted the important role that non-somatic compartments of neurons (axons and synapses) play in the instigation and progression of NCL pathogenesis. Here, we report a progressive breakdown of axons and synapses in the brains of two different mouse models of NCL: Ppt1(-/-) model of infantile NCL and Cln6(nclf) model of variant late-infantile NCL. Synaptic pathology was evident in the thalamus and cortex of these mice, but occurred much earlier within the thalamus. Quantitative comparisons of expression levels for a subset of proteins previously implicated in regulation of axonal and synaptic vulnerability revealed changes in proteins involved with synaptic function/stability and cell-cycle regulation in both strains of NCL mice. Protein expression changes were present at pre/early-symptomatic stages, occurring in advance of morphologically detectable synaptic or axonal pathology and again displayed regional selectivity, occurring first within the thalamus and only later in the cortex. Although significant differences in individual protein expression profiles existed between the two NCL models studied, 2 of the 15 proteins examined (VDAC1 and Pttg1) displayed robust and significant changes at pre/early-symptomatic time-points in both models. Our study demonstrates that synapses and axons are important early pathological targets in the NCLs and has identified two proteins, VDAC1 and Pttg1, with the potential for use as in vivo biomarkers of pre/early-symptomatic axonal and synaptic vulnerability in the NCLs.

Impact of cecostomy and antegrade colonic enemas on management of fecal incontinence and constipation: ten years of experience in pediatric population.

BACKGROUND: In childhood and adolescence, fecal soiling represents a psychologically devastating problem. Physical and emotional distress associated with daily rectal enemas is minimized by the introduction of a cecostomy tube for colonic cleansing with antegrade colonic enemas (ACEs). PATIENTS AND METHODS: Over a period of 10 years (1997-2007), we performed "button" cecostomies in 69 pediatric patients with fecal soiling secondary to a variety of disorders; laparoscopic procedures were performed in 40 and open procedures in 29. Mean postoperative follow-up was 4.03 SD +/- 1.76 years. Cleansing protocols differed between patients. RESULTS: We adopted a standardized questionnaire concerning management of incontinence/intractable constipation before and after button cecostomy insertion to assess the long-term impact of ACE on symptom severity and quality of life. Complications included tube dislodgement (n = 9), development of granulation tissue (n = 11), decubitus ulcer (n = 5), and infection (n = 3). Patient/parents satisfaction (appraisal scale 1-3) and improvement of quality of life achieved statistical significance for both (P < .001). CONCLUSIONS: Since button cecostomy and ACE were introduced in our institution as a management option, the treatment of fecal incontinence and intractable constipation significantly improved in terms of efficacy and patient compliance and also resulted in greater patient and parent satisfaction.