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Background: Diabetes-prone (DP) congenic DR.lyp/lyp BioBreeding (BB) rats all develop Type 1 diabetes between 50 and 81 days of age, while DR.lyp/+ or DR.+/+ BB rats are diabetes resistant (DR). The DP rats display reduced weight gain prior to developing hyperglycemia, implying that metabolic events may precede diabetes onset. We tested the hypothesis that temperature measurements could serve as a physiological marker for the impending onset of hyperglycemia. Methods: Prior to the onset of hyperglycemia, brain, lower back, and intrascapular brown adipose tissue temperatures were analyzed by thermal signature analysis, which measures infrared emission from tissues. A thermocoupled rectal probe measured core temperature. In addition we performed a beta(3)-adrenergic receptor challenge test with the beta(3)-adrenergic receptor agonist BRL37344. Results: DP rats displayed lower core temperature than DR rats prior to the onset of hyperglycemia. No temperature difference was detected in brain, lower back, or intrascapular brown adipose tissue between DP and DR rats. The beta(3)-adrenergic challenge showed that the rate of temperature increase after administration of BRL37344 was significantly higher (0.005 +/- 0.002 degrees C/min) in DP than in DR rats (P = 0.044). Conclusions: These studies reveal that the prediabetic DP rats fail to maintain core temperature and that they display increased sensitivity to heat production induced by a beta(3)-adrenergic receptor agonist. These studies suggest that body temperature as a measure of metabolic dysregulation is altered in the prediabetic DP rat prior to the onset of hyperglycemia. [ABSTRACT FROM AUTHOR]

Purpose: Genome sequencing (GS)-specific diagnostic rates in prospective tightly ascertained exome sequencing (ES)-negative intellectual disability (ID) cohorts have not been reported extensively., Methods: ES, GS, epigenetic signatures, and long-read sequencing diagnoses were assessed in 74 trios with at least moderate ID., Results: The ES diagnostic yield was 42 of 74 (57%). GS diagnoses were made in 9 of 32 (28%) ES-unresolved families. Repeated ES with a contemporary pipeline on the GS-diagnosed families identified 8 of 9 single-nucleotide variations/copy-number variations undetected in older ES, confirming a GS-unique diagnostic rate of 1 in 32 (3%). Episignatures contributed diagnostic information in 9% with GS corroboration in 1 of 32 (3%) and diagnostic clues in 2 of 32 (6%). A genetic etiology for ID was detected in 51 of 74 (69%) families. Twelve candidate disease genes were identified. Contemporary ES followed by GS cost US$4976 (95% CI: $3704; $6969) per diagnosis and first-line GS at a cost of $7062 (95% CI: $6210; $8475) per diagnosis., Conclusion: Performing GS only in ID trios would be cost equivalent to ES if GS were available at $2435, about a 60% reduction from current prices. This study demonstrates that first-line GS achieves higher diagnostic rate than contemporary ES but at a higher cost., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Rationale: Recent data show that Aspergillus species are prevalent respiratory infections in children with cystic fibrosis (CF). The biological significance of these infections is unknown. Objectives: We aimed to evaluate longitudinal associations between Aspergillus infections and lung disease in young children with CF. Methods: Longitudinal data on 330 children participating in the Australian Respiratory Early Surveillance Team for Cystic Fibrosis surveillance program between 2000 and 2018 who underwent annual chest computed tomography (CT) imaging and BAL were used to determine the association between Aspergillus infections and the progression of structural lung disease. Results were adjusted for the effects of other common infections, associated variables, and repeated visits. Secondary outcomes included inflammatory markers in BAL, respiratory symptoms, and admissions for exacerbations. Measurements and Main Results: Haemophilus influenzae , Staphylococcus aureus , Pseudomonas aeruginosa , and Aspergillus infections were all associated with worse CT scores in the same year ( P overall  < 0.05). Only P. aeruginosa and Aspergillus were associated with progression in CT scores in the year after an infection and worse CT scores at the end of the observation period. P. aeruginosa was most significantly associated with development of bronchiectasis (difference, 0.9; 95% confidence interval, 0.3-1.6; P  = 0.003) and Aspergillus with trapped air (difference, 3.2; 95% confidence interval, 1.0-5.4; P  = 0.004). Aspergillus infections were also associated with markers of neutrophilic inflammation ( P  < 0.001) and respiratory admissions risk ( P  = 0.008). Conclusions: Lower respiratory Aspergillus infections are associated with the progression of structural lung disease in young children with CF. This study highlights the need to further evaluate early Aspergillus species infections and the feasibility, risk, and benefit of eradication regimens.

In children with cystic fibrosis (CF) the associations between oropharyngeal swabs (OPSs) for detection of Pseudomonas and lung disease have not been evaluated.OPS and bronchoalveolar lavage (BAL) samples were obtained annually in children with CF from 2005 to 2017. OPS test characteristics were calculated using BAL as "gold standard". Results were related to lung inflammation (BAL neutrophil elastase and interleukin-8), structural lung disease (chest computed tomography PRAGMA-CF (Perth-Rotterdam Annotated Grid Morphometric Analysis for CF) scores), respiratory exacerbations and future detection of Pseudomonas on BAL.From 181 patients, 690 paired OPS-BAL cultures were obtained. Prevalence of Pseudomonas in BAL was 7.4%. OPS sensitivity was 23.0% and specificity was 91.4%, reducing the post-test probability for a positive BAL following a negative OPS to 6.3%. Pseudomonas on OPS was not associated with lung inflammation or respiratory exacerbations, but was weakly associated with current PRAGMA-CF %Disease score (p=0.043). Pseudomonas on BAL was associated with positive neutrophil elastase (OR 4.17, 95% CI 2.04-8.53; p<0.001), increased interleukin-8 (p<0.001), increased all baseline PRAGMA computed tomography scores (p<0.001), progression of PRAGMA computed tomography scores (p<0.05) and increased risk of respiratory exacerbations (incidence rate ratio 2.11, 95% CI 1.15-3.87; p=0.017).In children with CF OPSs only marginally change the probability of detecting lower airway Pseudomonas and are not associated with lung disease indices nor exacerbations risk., Competing Interests: Conflict of interest: None declared., (Copyright ©ERS 2018.)

GABA (γ-aminobutyric acid), the main inhibitory neurotransmitter in the central nervous system is also present in the pancreatic islet β cells where it may function as a paracrine molecule and perhaps as an immunomodulator of lymphocytes infiltrating the pancreatic islet. We examined CD4(+) and CD8(+) T cells from diabetes prone (DR(lyp/lyp)) or resistant (DR(+/+)) congenic biobreeding (BB) rats for expression of GABA(A) channels. Our results show that BB rat CD4(+) and CD8(+) T cells express α1, α2, α3, α4, α6, β3, γ1, δ, ρ1 and ρ2 GABA(A) channel subunits. In CD8(+) T cells from DR(lyp/lyp) animals the subunits were significantly upregulated relative to expression levels in the CD8(+) T cells from DR(+/+) rats as well as from CD4(+) T cells from both DR(lyp/lyp) and DR(+/+) rats. Functional channels were formed in the T cells and physiological concentrations of GABA (100 nM) decreased T cell proliferation. Our results are consistent with the hypothesis that GABA in the islets of Langerhans may diminish inflammation by inhibition of activated T lymphocytes., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Aim: The BB rat model of type 1 diabetes exhibits altered body weight gain and body temperature regulation prior to hyperglycemia onset, implying the existence of as yet unidentified biomarkers of autoimmune processes that destroy pancreatic beta cells. To investigate this hypothesis, we compared the metabolic profile of diabetes-resistant DR.lyp/+ rats and their diabetes-prone, congenic DR.lyp/lyp littermates in the days leading up to diabetes onset., Methods: Except for the Gimap5 mutation on chromosome 4, congenic DR.lyp/lyp rats are genetically identical to DR.lyp/+ littermates. They invariably develop hyperglycemia at 46-81 days of age, whereas DR.lyp/+ rats do not develop diabetes. In addition to daily food intake and body weight, indirect calorimetry was performed continuously on male DR.lyp/lyp and DR.lyp/+ rats (n=6/group) for 6-18 days to measure locomotor activity, VO (2), VCO (2) and RQ., Results: DR.lyp/lyp rats exhibited a progressive decrease of RQ compared to DR.lyp/+ rats 0.005+/-0.001 units/day (p<0.005). Limiting the analysis to the six days prior to diabetes onset revealed a larger decrease of 0.007+/-0.002 units/day (p<0.001) in DR.lyp/lyp animals, whereas RQ of the DR.lyp/+ rats remained unchanged. This metabolic change occurred prior to hyperglycemia onset and was not associated with changes of any other parameter., Conclusions: Diabetes onset in DR.lyp/lyp rats is heralded by a progressive shift towards lipid oxidation relative to carbohydrate metabolism.

The neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are structurally and functionally related. Their actions have been shown to be mediated by three different receptor subtypes: PAC1-R, which has exclusive affinity for PACAP, and VPAC1-R and VPAC2-R, which have equal affinity for PACAP and VIP. We recently showed that PACAP38 induces lipolysis in rat adipocytes, and in the present study we examined whether VIP has similar effects and which of the three receptors mediates this PACAP/VIP action. We showed by RT-PCR that all three receptor subtypes are present in rat adipocytes. We demonstrated that VIP (1-100 nm), like PACAP38, stimulates lipolysis in isolated adipocytes, as determined by glycerol release. By a pharmacological approach, using antagonists and agonists specific for the receptor subtypes, we elucidated the mechanisms by which PACAP38 and VIP mediate their lipolytic effects. We found that antagonists of PAC1-R [PACAP(6-38)] and VPAC1-R (PG97-269) did not affect lipolysis induced by 0.1-100 nm PACAP38 or VIP, and that a VPAC1-R agonist [K15, R16, L27VIP(1-7)GRF(8-27)] did not affect lipolysis at 1-1000 nm. However, two different VPAC2-R agonists [Hexa-VIP(1-28) and Ro25-1553] clearly mimicked the lipolytic effect of PACAP38 and VIP. In addition, the VPAC2-R antagonist PG99-465 (100 nm) caused right-shifted dose-response curves of PACAP38- and VIP-induced lipolysis. These results therefore provide evidence that all three PACAP/VIP receptor subtypes are expressed in primary rat adipocytes, but that the VPAC2-R subtype is responsible for mediating the lipolytic effects induced by PACAP38 and VIP.

DNA fragments containing mispaired and modified bases, bulges, lesions and specific sequences have altered conformation. Methods for separating complex samples of DNA fragments based on conformation but independent of length have many applications, including (i) separation of mismatched or unmatched DNA fragments from those perfectly matched; (ii) simultaneous, diagnostic, mismatch scanning of multiple fragments; (iii) isolation of damaged DNA fragments from undamaged fragments; and (iv) estimation of reannealing efficiency of complex DNA samples. We developed a two-dimensional conformation-dependent electrophoresis (2D-CDE) method for separating DNA fragments based on length and conformation in the first dimension and only on length in the second dimension. Differences in migration velocity due to conformation were minimized during second dimension electrophoresis by introducing an intercalator. To test the method, we constructed 298 bp DNA fragments containing cytosine bulges ranging from 1 to 5 nt. Bulge-containing DNA fragments had reduced migration velocity in the first dimension due to altered conformation. After 2D-CDE, bulge-containing DNA fragments had migrated in front of an arc comprising heterogeneous fragments with regular conformation. This simple and robust method could be used in both analytical and preparative applications involving complex DNA samples.

Software packages are widely used for quantification of myocardial perfusion defects. The quantification is used to assist the physician in his/her interpretation of the study. The purpose of this study was to compare the quantification of reversible perfusion defects by three different commercially available software packages. We included 50 consecutive patients who underwent myocardial perfusion single-photon emission tomography (SPET) with a 2-day technetium-99m tetrofosmin protocol. Two experienced technologists processed the studies using the following three software packages: Cedars Quantitative Perfusion SPECT, Emory Cardiac Toolbox and 4D-MSPECT. The same sets of short axis slices were used as input to all three software packages. Myocardial uptake was scored in 20 segments for both the rest and the stress studies. The summed difference score (SDS) was calculated for each patient and the SDS values were classified into: normal (< 4), mildly abnormal (4-8), moderately abnormal (9-13), and severely abnormal (> 13). All three software packages were in agreement that 21 patients had a normal SDS, four patients had a mildly abnormal SDS and one patient had a severely abnormal SDS. In the remaining 24 patients (48%) there was disagreement between the software packages regarding SDS classification. A difference in classification of more than one step between the highest and lowest scores, for example from normal to moderately abnormal or from mildly to severely abnormal, was found in six of these 24 patients. Widely used software packages commonly differ in their quantification of myocardial perfusion defects. The interpreting physician should be aware of these differences when using scoring systems.

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide that exerts its effects throughout the body by elevating the intracellular amounts of cAMP. In adipocytes, an increased amount of cAMP is associated with increased lipolysis. In this work we evaluated the effects of PACAP38 on triglyceride metabolism in primary rat adipocytes. Stimulation of adipocytes with PACAP (0.1-100 nm) resulted in stimulation of lipolysis to the same extent as isoproterenol. Lipolysis was blocked by 25 microm of the protein kinase A inhibitor H-89 and potentiated in the presence of 10 microm OPC3911, a phosphodiesterase 3 inhibitor. In addition, PACAP38 induced activation of protein kinase A. Insulin efficiently inhibited PACAP38-induced lipolysis in a phosphatidyl inositol 3-kinase and phosphodiesterase 3-dependent manner. Interestingly, we also found that PACAP38, as well as isoproterenol, induced potentiation of lipogenesis in the presence of insulin. These results show that PACAP38 and isoproterenol mediate catabolic as well as anabolic effects in adipocytes, depending on the concentration of insulin present. We speculate that in the early postprandial state and during fasting, when insulin levels are low, PACAP and beta-adrenergic catecholamines induce lipolysis, whereas when higher levels of insulin are present, these agents potentiate the anabolic effect of insulin, i.e. storage of triglycerides.

Universal varicella-zoster virus (VZV) childhood vaccination is still debated, but adult chickenpox may be severe. It could be prevented by vaccination of seronegative adolescents. This study aimed to determine the feasibility of coadministration of a VZV vaccine and the measles-mumps-rubella (MMR) booster at 12 y of age. Guardians of 1231 12-y-old pupils where asked about the history of chickenpox in their children. 190 had no chickenpox history and 12 of 62 of them lacked VZV antibodies. Additional history-negative children were also recruited. 199 history-positive children received only MMR and 98 history-negative children received an MMR vaccine and a VZV vaccine. Serum samples were drawn before vaccination and after 8 weeks. Viral antibodies were measured by immunofluorescence (VZV) and enzyme-linked immunosorbent assays (VZV, MMR). All 184 history-positive children tested had VZV antibodies. 17/89 VZV-vaccinated and tested children (19%) lacked VZV antibodies before vaccination. 12 (71%) seroconverted after 1 dose. Cell-mediated immunity (CMI) against varicella was tested in 3/5 children who did not seroconvert after 1 dose of VZV vaccine. They seroconverted after a second dose and had measurable CMI. VZV vaccination did not affect the MMR response and there were no severe side-effects. A history of varicella infection, as reported by the guardian, is reliable, but a negative history was incorrect in 81% of the cases. This population of 12-y-old children may require 2 doses of VZV vaccine, at least when given simultaneously with the MMR vaccine.

Objective: The purpose of this study was to compare magnetic resonance (MR) imaging and surgical observations of fluid in simple bone cysts., Study Design: Findings during MR imaging of 7 simple bone cysts were compared with surgical observations 1 day or 1.8 months (mean) after MR imaging., Results: All MR images showed cavities filled with fluid. In 2 patients operated on the day after the imaging, surgical observations were in accordance with the MR findings. At surgery 1.8 months after the MR examination, 4 cavities were found to be empty and 1 cavity contained only a minor amount of fluid., Conclusion: A discrepancy between MR imaging and surgical observations of fluid in simple bone cyst cavities was observed that might be dependent on the time between the observations, indicating that a fairly rapid absorption of fluid might occur or that the amount of fluid in a simple bone cyst can vary for unknown reasons.

Background: In earlier studies of vertical banded gastroplasty (VBG), staple-line disruptions (SD) were only reported in a few per cent or less. Two recent studies have shown a significantly higher frequency of SD. To find the true frequency of SD, all patients must be examined regardless of weight outcome., Methods: 91 consecutive patients were examined by a standardized radiological method at different postoperative intervals ranging from 6 to 48 months., Results: 41 out of 91 patients developed SD. The average diameter of the disruptions was 6 mm (range 2-16 mm). During the first 2 years of follow-up, when at least 31% of the patients had developed SD, there was no significant difference in weight loss between the group with SD and the group without SD., Conclusion: SD is an inherent problem of VBG which has been underestimated for a long period of time. An SD frequency of 45% or more within the first few years is not acceptable and changes in the VBG technique must be considered.

The diagnostic image quality of panoramic radiographs originating from different clinics was examined. Two samples of 98 and 100 radiographs, respectively, were from a department of oral radiology. The radiographs of one of these samples were checked using immediate subjective analysis of the image quality before inclusion in the study whereas the radiographs of the other sample were randomly selected. A third sample consisted of radiographs from 20 randomly selected dental clinics. The subjective overall image quality of the whole panoramic radiograph was classified as adequate, marginal or inadequate. The three observers also assessed the reason for inferior image quality. The overall image quality of the radiographs was better for the checked sample from the department of oral radiology compared to the sample form the 20 dental clinics. The main reason for unacceptable image quality of the radiographs was too low density and/or contrast irrespective of sample. Other faults were incorrect positioning of the patient but in the sample from the 20 clinics improper film handling was also frequent. We conclude that image quality in panoramic radiography can be improved. Improvement of the image quality is a prerequisite if panoramic radiography in the future is to replace the full-mouth examination.

Panoramic, bitewing and periapical radiography and probing for measurement of the marginal bone level were compared. Altogether 237 sites of 23 patients were examined. Radiographs were taken with a splint containing steel balls to allow calculation of the enlargement of the radiographs. Probing was done before and during flap surgery using the same splint. The open bone measurement represented the true value. All radiographs were assessed by 5 observers. The mean enlargement of panoramic radiography was 27% in the upper and 26% in the lower arch. For bitewing and periapical radiography, it was 8% in the upper and 4-5% in the lower arch. All methods underestimated the bone loss. Probing bone level before surgery was most accurate, deviating at most 5% from the true value. Periapical radiography was more accurate than panoramic and bitewing radiography (p less than 0.001). Panoramic radiography presented a slightly lower mean accuracy than bitewing radiography (p less than 0.05). The underestimation of the bone loss ranged from 13 to 32% in orthopantomograms, 11-23% in bitewing and 9-20% in periapical radiographs. The interobserver variation of the radiographic methods was substantial.

The aim of this study was to investigate both the actual and the radiographic tooth lengths of the maxillary first molar and second premolar and the mandibular premolars in panoramic radiographs. The actual length of 64 extracted teeth was measured. Steel balls were then attached to the cusp and apex and the teeth embedded in plastic moulds. Each pair of plaster casts with their set of teeth was radiographed with an Orthopantomograph twice at an interval of 1 month. The actual and the radiographic tooth length was measured twice by one observer. The mean tooth length of the molar was shorter than that of the premolars. The mean difference between the repeated measurements of the actual tooth length was small and ranged between 0.47 and 1.16% of the tooth length. The mean difference between repeated measurements of the radiographic tooth length was also small, with a method error of 0.13-0.21 mm. The vertical magnification in panoramic radiography was lower for mandibular premolars (13-15%) than for the maxillary second premolar and first molar (17-28%). The palatal root of the maxillary first molar had the highest vertical magnification (28%). Following the second set of radiographs, the mean difference between the measurements was small, except for the palatal root of the maxillary first molar (P < 0.001). Radiographic measurements of this root should therefore be used with caution. The results for the other roots examined indicate that these could be measured with high reproducibility.

Methods based on radiological, distinguishable stages of tooth formation can be used to estimate chronological age in young persons. The best precision and accuracy of these methods of age estimation is obtained when many teeth are under development and when the individual growth rate is rapid. That is during early years-in childhood. After an age of about 14 years it becomes more difficult since all permanent teeth but the wisdom teeth have completed their development and only these remain to be used for age estimation. The aim of this study was to examine the radiological development of the root of the mandibular third molar and to explore its usefulness in age estimation. Also the differences between two independent observers were studied. The observers classified the development of the mandibular third molars, as seen in a panoramic radiograph, into seven defined stages. The two observers agreed in about 84% of the cases in their registration of the different stages, but a significant difference was found between the observers. The mineralisation of the third molar's root was found to start at the age of 15 years and the root was fully formed at about 20 years. Some minor differences were found between sexes in the time sequence of the mineralisation. The study also shows that there is a rather low precision in the age estimation with the method used. In general, a standard deviation of about 1 to 2 years was found around the mean age of the different developmental stages.

The radiation dosage for the Orthopantomograph model OP5 was measured using two different sizes of collimators. The concordance between and accuracy of panoramic radiography and periapical and bitewing radiography was examined regarding assessment of the marginal bone level. The measurability of panoramic and periapical and bitewing radiographs was compared, as was the image quality of panoramic radiographs from one selected sample and two random samples. The energy imparted was 0.4-0.8 mJ for one panoramic radiograph. The use of the narrow collimator reduced the dosage by about one-third. The concordance between panoramic and intraoral radiography was high. In some anatomical regions, the concordance was as high as the intraobserver agreement for one and the same technique. The concordance was lower in sites with severe bone loss, however. Sounding was very accurate for the measurement of the marginal bone loss. Of the radiographic techniques, periapical radiography was most accurate. The observer performance for linear measurements of bone loss varied substantially and systematically among five observers. The measurability in the upper arch was the same in panoramic and periapical radiography. In the lower arch, the measurability of periapical radiography was better. The image quality of panoramic radiography influenced the measurability. The image quality of panoramic radiographs from random samples was inferior to that of the selected sample. It was concluded that, for the assessment of the marginal bone level, the panoramic radiograph should be the radiographic examination of choice, if increased image quality is achieved.

Panoramic and periapical radiography was performed on 100 patients. Five observers each registered the scores for marginal bone level, presence of bone defects and furcation involvement in the radiographs of 20 patients and the results were compared. The overall concordance in scoring the marginal bone level was high when panoramic and periapical radiography was compared. In the upper arch, 66% of the sites showed concordant scores, 31% deviated by one and 3% by two score-points. In the lower arch, 74% of sites had concordant scores, 25% deviated by one and 1% by two score-points. The panoramic radiographs more often indicated a more severe bone loss than the periapical radiographs. The concordance was related to the degree of bone loss. In sites with no bone loss the concordance was high whereas it was lower in those with severe bone loss. The concordance of the two radiographic methods for the mandibular canine, premolars and first molar was equally as high as the intra-observer overall agreement, but lowest for the mandibular central incisors and the maxillary molars. Bone defects were more easily identified by periapical radiography.

Five observers assessed the panoramic and full-mouth (14 periapical and four posterior bitewing) radiographs of 20 patients each for the ability to interpret and measure the marginal bone level. The image quality of each site was classified as excellent, acceptable or unacceptable. Depiction errors affecting interpretability and measurability were also noted. In the upper arch, the frequency of uninterpretable and non-measurable sites was almost equal for panoramic and periapical radiography. Image quality was better with periapical radiography in the lower arch. In the posterior regions of both arches, more sites could not be measured from panoramic compared with bitewing radiographs. Due to overlapping the distal surface of the maxillary canine and the mesial surface of the first maxillary premolar could often not be interpreted in either panoramic or periapical radiographs, but infrequently in the bitewings. In the lower arch, the most frequent depiction error was inadequate density in the incisor region of panoramic radiographs. On the basis of these results, we proposed that in clinical practice the panoramic radiograph can be supplemented with individually selected periapicals. In epidemiological studies, the panoramic radiograph should be combined with a premolar bitewing radiograph.