The tellurium-based immunomodulator, AS101 ameliorates adjuvant-induced arthritis in rats.

Despite undeniable improvement in the management of rheumatoid arthritis (RA), the discovery of more effective, less toxic and, ideally, less immune suppressive drugs are much needed. In the current study, we set to explore the potential anti-rheumatic activity of the non-toxic, tellurium-based immunomodulator, AS101 in an experimental animal model of RA. The effect of AS101 was assessed on adjuvant-induced arthritis (AIA) rats. Clinical signs of arthritis were assessed. Histopathological examination was used to assess inflammation, synovial changes and tissue lesions. Very late antigen-4 (VLA-4)+ cellular infiltration was detected using immunohistochemical staining. Enzyme-linked immunosorbent assay (ELISA) was used to measure circulating anti-cyclic citrullinated-peptide autoantibody (ACPA) and real-time polymerase chain reaction (PCR) was used to measure the in-vitro effect of AS101 on interleukin (IL)-6 and IL-1ß expression in activated primary human fibroblasts. Prophylactic treatment with intraperitoneal AS101 reduced clinical arthritis scores in AIA rats (P < 0·01). AS101 abrogated the migration of active chronic inflammatory immune cells, particularly VLA-4+ cells, into joint cartilage and synovium, reduced the extent of joint damage and preserved joint architecture. Compared to phosphate-buffered saline (PBS)-treated AIA rats, histopathological inflammatory scores were significantly reduced (P < 0·05). Furthermore, AS101 resulted in a marked reduction of circulating ACPA in comparison to PBS-treated rats (P < 0·05). Importantly, AS101 significantly reduced mRNA levels of proinflammatory mediators such as IL-6 (P < 0·05) and IL-1ß (P < 0·01) in activated primary human fibroblasts. Taken together, we report the first demonstration of the anti-rheumatic/inflammatory activity of AS101 in experimental RA model, thereby supporting an alternative early therapeutic intervention and identifying a promising agent for therapeutic intervention.

The influence of the SARS-CoV-2 lockdown on patients with inflammatory rheumatic diseases on their adherence to immunomodulatory medication: a cross sectional study over 3 months in Germany.

OBJECTIVES: To evaluate the influence of the SARS-CoV-2 pandemic on the adherence of patients with inflammatory rheumatic diseases (IRD) to their immunomodulatory medication during the three-month lockdown in Germany. METHODS: From 16th March until 15th June 2020, IRD patients from private practices and rheumatology departments were asked to answer a questionnaire addressing their behaviour with respect to their immunomodulating therapy. Eight private practices and nine rheumatology departments that included rheumatology primary care centres and university hospitals participated. A total of 4252 questionnaires were collected and evaluated. RESULTS: The majority of patients (54%) were diagnosed with RA, followed by psoriatic arthritis (14%), ankylosing spondylitis (10%), connective tissue diseases (12%) and vasculitides (6%). Most of the patients (84%) reported to continue their immunomodulatory therapy. Termination of therapy was reported by only 3% of the patients. The results were independent from the type of IRD, the respective immunomodulatory therapy and by whom the patients were treated (private practices vs rheumatology departments). Younger patients (<60 years) reported just as often as older patients to discontinue their therapy. CONCLUSION: The data show that most of the patients continued their therapy in spite of the pandemic. A significant change in behaviour with regard to their immunomodulatory therapy was not observed during the three months of observation. The results support the idea that the immediate release of recommendations of the German Society of Rheumatology were well received, supporting the well-established physician-patient relationship in times of a crisis.

Atopic dermatitis, STAT3- and DOCK8-hyper-IgE syndromes differ in IgE-based sensitization pattern.

BACKGROUND: Increased serum IgE levels are characteristic but not specific for allergic diseases. Particularly, severe atopic dermatitis (AD) overlaps with hyper-IgE syndromes (HIES) regarding eczema, eosinophilia, and increased serum IgE levels. HIES are primary immunodeficiencies due to monogenetic defects such as in the genes DOCK8 and STAT3. As it is not known to date why allergic manifestations are not present in all HIES entities, we assessed the specificity of serum IgE of AD and HIES patients in the context of clinical and immunological findings. METHODS: Clinical data, skin prick tests, specific IgE to aero- and food allergens, and T helper (Th) subpopulations were compared in AD and molecularly defined HIES patients. RESULTS: Total serum IgE levels were similarly increased in STAT3-HIES, DOCK8-HIES, and AD patients. The ratio of aeroallergen-specific IgE to total IgE was highest in AD, whereas DOCK8-HIES patients showed the highest specific serum IgE against food allergens. Overall, clinical allergy and skin prick test results complied with the specific IgE results. Th2-cell numbers were significantly increased in DOCK8-HIES and AD patients compared to STAT3-HIES patients and controls. AD patients showed significantly higher nTreg-cell counts compared to STAT3-HIES and control individuals. High Th17-cell counts were associated with asthma. Specific IgE values, skin prick test, and T-cell subsets of STAT3-HIES patients were comparable with those of healthy individuals except decreased Th17-cell counts. CONCLUSION: Hyper-IgE syndromes and atopic dermatitis patients showed different sensitization pattern of serum IgE corresponding to the allergic disease manifestations and Th-cell subset data, suggesting a key role of DOCK8 in the development of food allergy.

Wnt signalling in Caenorhabditis elegans: regulating repressors and polarizing the cytoskeleton.

Wnt proteins are secreted, cysteine-rich glycoprotein ligands with numerous roles during animal development. Recent studies of endoderm induction during embryogenesis in the nematode Caenorhabditis elegans challenge the prevailing view that Wnt signalling specifies cell fate by converting transcriptional repressors into activators. Instead, a mitogen-activated protein kinase (MAPK)-related pathway converges with Wnt signalling in C. elegans to relieve transcriptional repression. Furthermore, Wnt signalling induces endoderm in part by aligning the mitotic spindle in a responding cell along the anterior-posterior body axis. To orient mitotic spindles, Wnt signalling might directly target the cytoskeleton, prior to any regulation of gene transcription in responding cells.

First-year medical students' attitudes toward radiology.

To explore the perspectives of entering medical students, a questionnaire was completed anonymously by 171 students in September of their first year of medical school. The authors investigated their attitudes toward radiology relative to other specialties and their perspective concerning which factors would influence their eventual choice of a specialty. Upon entering medical school, 33.3% of the students indicated that they had chosen a specialty, and 7.4% of these students had selected radiology. Radiology was perceived as a well-paid specialty with a pleasant lifestyle. These are factors that were perceived as very important regarding influence on eventual choice of specialty. However, radiology was believed to have an undesirably low level of patient contact and was perceived as not being intellectually exciting. We plan to follow this group of students prospectively through medical school to see whether their attitudes change toward radiology as a career.

Carpo-metacarpal growth disturbance and the assessment of carpal narrowing in children with juvenile rheumatoid arthritis.

Second metacarpal length (M2), radio-metacarpal length (RM), and intermetacarpal width (W) were measured on 96 radiographs in 52 children with polyarticular juvenile rheumatoid arthritis (JRA), and compared with body height and skeletal maturation in order to: (1) differentiate between processes resulting in retardation of bone growth and those producing delay in skeletal maturation; (2) assess the severity and progression over time of such retardation; and (3) assess the impact of retardation of the second metacarpal on the assessment of carpal narrowing in children with JRA. All measurements were converted into z scores (the units of standard deviation above or below the normal mean for each measurement) based on published norms. Retardation of M2 (mean z scores -0.91) began earlier and was more severe compared with retardation of height (mean z score -0.25). This disproportion widened with increasing duration of disease. That this primarily represents a disturbance in M2 growth rather than a secondary effect due to altered maturation is suggested by the bone ages being normal (mean z score 0.14) and the absence of premature closure of the metacarpal physes. Z scores for RM/W (mean -3.53) were at least 1 Z more negative than for corresponding measurements of RM/M2 (mean -2.41) in 47 (90.4%) children and the mean difference between the z scores for RM/W was -1.12. This discrepancy between RM/W and RM/M2 was eliminated by correcting for the reduction in M2.

Postural control, attention and sleep deprivation.

We investigated the effect of sleep deprivation on postural control during a simple reaction time task (SRT), during a task requiring the intermittent inhibition of a reaction (IRT), and in the absence of a concurrent information processing task. Postural sway, i.e. changes in center of pressure on a force platform, was recorded in three increasingly difficult standing conditions (fixed platform, sway-referenced platform and sway-referenced platform with sway-referenced visual scene) during the three information-processing task conditions. Five healthy subjects performed the tasks either after normal sleep or following 24 h of sustained wakefulness. As hypothesized, sleep deprivation significantly increased postural sway only in the IRT condition. Within the IRT condition, sleep deprivation significantly increased sway across all postural conditions.

Concurrent hydromyelia and diastematomyelia.

Hydromyelia was discovered in six of 13 patients with diastematomyelia. In one patient, hydromyelia affected only the segments of spinal cord above the diastematomyelia. In five patients, hydromyelia extended downward from the single cord into one or both hemicords. Because hydromyelia and diastematomyelia occur simultaneously, because they may produce very similar clinical changes, and because simultaneous or sequential surgical correction of both conditions may be necessary to achieve the best clinical result, the possibility of hydromyelia should be evaluated specifically in each patient demonstrated to have diastematomyelia.

Home enteral nutrition in patients with Acquired Immunodeficiency Syndrome.

UNLABELLED: 14 patients in advanced stages of HIV infection (1 ARC, 13 AIDS; sex: 1 female, 13 male; age 37.8 +/- 6.3 years; body mass index (BMI): 17.4 +/- 2.4 kg/m(2)) were followed prospectively while receiving home enteral nutrition (observation period: 62 +/- 75 days). Artificial nutrition was indicated because of severe weight loss (9-38 kg within 6-48 months, n = 7) or cerebral toxoplasmosis with eating and swallowing disorders (n = 7). In all patients a defined formula diet (175 +/- 17.7 kJ/kg body weight) was administered through an endoscopically placed gastrostomy tube (PEG). Home enteral nutrition was well tolerated by all patients and no significant PEG-related complications occurred. Enteral nutrition resulted in significant increases in body weight (p < 0.005), body cell mass (BCM, p < 0.05), total body fat (TBF, p < 0.005), serum albumin concentration (p < 0.05), and serum total iron-binding capacity (transferrin, p < 0.01). CONCLUSION: Home enteral nutrition via PEG is safe and well tolerated in patients with advanced HIV-related immunodeficiency and is capable of improving nutritional state including BCM.

Radiographic lung disease and response of persistent pulmonary hypertension to mean airway pressure and alkalosis.

Persistent pulmonary hypertension of the newborn (PPHN) is associated with multiple cardiopulmonary diseases. Therapy often includes hyperventilation/alkalosis despite little evidence as to its efficacy in diverse conditions. To determine (1) if part of the improvement of arterial oxygen tension (PaO2) attributed to alkalosis is actually related to increased mean airway pressure (P(aw)) and (2) if the presence of radiographic pulmonary disease predicts the response to alkalosis or mean airway pressure, we reviewed records of 19 newborns with well-documented PPHN. Arterial blood gases and corresponding ventilator settings were recorded during the first day of life. To adjust for lower FiO2, corrected PaO2 (cPaO2) was calculated when the FiO2 < 1.0, such that cPaO2 = calculated arterial/alveolar oxygen ratio x (713 - PaCO2/0.8). Regression equations were obtained and mean slopes of these were compared for P(aw) vs. cPaO2, and pH vs. cPaO2 by one group t-tests (with assumed population slope of zero). There was no correlation between P(aw) and cPaO2 (mean slope +/- SD = -8.4 +/- 30.8, P = 0.25), but there was a moderate correlation between pH and cPaO2 (mean slope = 333.1 +/- 480.5, P = 0.007). Patients were then classified by chest radiographs as having severe or minimal/no lung disease. Relationships of P(aw) and pH to cPaO2 were then re-examined. No correlation was present between P(aw) and cPaO2 in 11 patients with PPHN and severe radiographic disease (mean slope = -7.4 +/- 26.9, P = 0.38) or in eight patients with PPHN and minimal/no lung disease (mean slope = -9.8 +/- 37.5, P = 0.48).(ABSTRACT TRUNCATED AT 250 WORDS)

Weight gain and increased concentrations of receptor proteins for tumor necrosis factor after patients with symptomatic HIV infection received fortified nutrition support.

OBJECTIVE: To determine whether certain nutrients and dietary factors act as modulators of the immune system and improve the nutritional status of immunocompromised patients. DESIGN: Controlled, double-blind, crossover phase trials of the effects of a fortified formula in patients infected with the human immunodeficiency virus (HIV). Patients consumed a control formula for 4 months and a study formula for 4 months. SUBJECTS: Ten men with symptomatic HIV infection who were following stable medication regimens and had no malignancies, mycobacteriosis, or additional virus infection requiring systemic treatment. INTERVENTION: Formula fortified with alpha-linolenic acid (1.8 g/day), arginine (7.8 g/day), and RNA (0.75 g/day) and a standard formula. MAIN OUTCOME MEASURES: Nutritional status determined by anthropometric, bioelectrical, biochemical, and dietary assessment; energy expenditure determined by indirect calorimetry; disease progression; CD4 lymphocyte counts; HIV p24 antigen plasma concentrations; tumor necrosis factor (TNF) receptor proteins; and compliance control parameters. STATISTICAL ANALYSES PERFORMED: Student's t tests for paired and unpaired data. RESULTS: Fortified nutrition resulted in a weight gain (+ 2.9 kg/4 months vs -0.5 kg/4 months with the control formula, P < .05), an incorporation of eicosaenoic acid into erythrocyte cell membranes (+ 47% of baseline values, P < .05), and increased plasma arginine concentrations (96.8 +/- 45.1 vs 51.8 +/- 20.9 mumol/L, P < .01). The serum concentrations of the soluble tumor necrosis factor receptor (sTNFR) proteins increased during the study period (sTNFR 55 = + 0.23 vs -0.40 ng/mL, P < .001; sTNFR 75 = + 0.90 vs -0.36 ng/mL, P < .01), whereas no changes in CD4+ lymphocyte counts were observed. CONCLUSION: Increasing dietary intakes of n-3 polyunsaturated fatty acids, L-arginine, and RNA increased body weight, possibly by modulating the negative effects of TNF.

Correlation of ultrasound with postmortem neuropathologic studies in neonates.

We examined the correlation between cranial sonogram and postmortem examination neurodiagnoses in 51 infants (30 boys and 21 girls) who underwent cranial sonogram before death. The mean gestation of the infants at birth was 32 weeks 6 days; the mean birth weight, 1,992 gm; and the mean survival, 27 days. Most infants had several postmortem examination neurodiagnoses; therefore the postmortem examination diagnosis considered to be most significant in terms of clinical management and long-term neurologic function was chosen for each infant and designated as the primary diagnosis. The ability of the cranial sonogram to diagnose the primary diagnosis was then evaluated. The accuracy of the cranial sonogram in defining primary diagnoses was 59%. There were 21 cases (41%) in which cranial sonogram failed to define the primary diagnosis; nine of these could be explained on the basis of the timing of the ultrasound in relation to the age of the lesion or to the microscopic nature of the lesion. In 12 patients the factors causing the failure of cranial sonogram to define primary postmortem examination diagnoses could not be identified. The positive predictive value of a cranial sonogram diagnosis was 77%; the negative predictive value was 19%.

Medical students' attitudes toward radiology: comparison of matriculating and graduating students.

RATIONALE AND OBJECTIVES: To determine graduating medical students' perceptions of radiology and to document changes in their perceptions since they entered medical school. MATERIALS AND METHODS: A survey questionnaire was distributed to 213 graduating students. Questions were similar to those answered by the same group of students as they entered medical school nearly 4 years earlier. RESULTS: The survey was anonymously completed by 140 students. Seventy percent of students changed their choice of medical specialty since entering medical school. Factors with a major or important influence on specialty choice included intellectual excitement (96%), high patient contact (86%), opportunity for a good family life (72%), and regular hours (57%). Radiology was perceived to be a well-paid (89%), "high-tech" (86%) specialty with a healthy lifestyle (82%), regular hours (99%), and good family life (92%), but it was not perceived to offer high patient contact (1%) and was intellectually exciting to only 33% of students. This perception was unchanged from freshman year. CONCLUSIONS: This 4-year longitudinal study of a medical student class documents surprisingly little change in the perception of radiology throughout medical school. High patient contact and intellectual excitement, both factors of major or important influence on specialty choice, were thought to be lacking in radiology.

Performance on the radiology component of a critical clinical skills examination.

RATIONALE AND OBJECTIVES: Clinical competence certification is now required in some specialties in medicine. A Comprehensive Clinical Assessment (CCA) was created to test mastery of critical skills by students at the end of the 3rd year of medical school. METHODS: The CCA is a series of stations that test skills the faculty consider important for all medical students (eg, breast examination, electrocardiogram reading, chest pain assessment, ophthalmology photographs). The radiology station was designed to evaluate imaging skills believed to be taught and learned in the core 3rd-year rotations. RESULTS: External measures (National Board Examinations, grade point average, and overall score) of clinical performance of the 608 medical students who completed the CCA examination between 1991 and 1993 were found to be correlated with the radiology station scores. CONCLUSION: The radiology station in the CCA examination is a reproducible measure of clinical performance.

Variability in Cobb angle measurements in children with congenital scoliosis.

The variability in measurement of angles in congenital scoliosis is not known, but it is postulated that it is larger than that in adolescent idiopathic scoliosis due to skeletal immaturity, incomplete ossification, and anomalous development of the end-vertebrae. To determine this variability, we selected 54 radiographs of adequate quality showing 67 scoliotic curves from children with congenital scoliosis. The end-vertebrae were preselected. Each curve was measured by the Cobb method on two separate occasions by six different observers, using the same goniometer and marker. The intraobserver variability was +/- 9.6 degrees and the interobserver variability +/- 11.8 degrees. If 'significant progression' is to be used as a criterion for surgical fusion in congenital scoliosis, there should be at least a 23 degrees increase, the entire range of the interobserver variability, in the curvature to ensure that the perceived increase is not due to variability in measurement.

Resolution of splenic injury after nonoperative management.

Numerous studies have demonstrated success with nonoperative management of splenic injuries in pediatric patients. However, the resolution of the splenic injury has not been previously evaluated. The records of 50 pediatric patients with splenic injuries from blunt trauma treated nonoperatively between 1984 to 1992 were reviewed retrospectively. Abdominal computed tomography (CT) was performed at the time of injury and 6 weeks postinjury in 25 patients. These scans were reviewed and categorized by a modification of a previously reported grading system for parenchymal injury. All patients had healing of the splenic injuries, with complete resolution of the healing process observed at 6 weeks postinjury in 44%. Even those with shattered spleens (n = 6) had consistent improvement in splenic architecture, with resolution of fractures and/or contusions and return of splenic perfusion. Ten (77%) of 13 grade 1 and 2 injuries were completely resolved by the 6-week follow-up examination, whereas only one (8%) of 12 grade 3 to 5 injuries showed radiological resolution of splenic injuries. None of the 25 follow-up CT scans affected clinical decision-making or led to a deviation from the established protocol, which included a 3-month period of reduced activity. All 50 patients did well, without evidence of morbidity, mortality, or complications after return to full activity 3 months postinjury.(ABSTRACT TRUNCATED AT 250 WORDS)

Utility of sonography in the diagnosis of bronchopulmonary sequestration.

Sonography in six patients with pulmonary sequestration demonstrated findings associated with and indicative of that diagnosis. The most useful feature, which was seen in three cases and is diagnostic of sequestration, is the identification of an anomalous systemic artery arising from the aorta.

Radiographic imaging of airway obstruction in pediatrics.

The authors review techniques available to image the airway, normal radiographic airway anatomy, pitfalls in imaging the airway, and radiographic findings in various pathologic processes that may cause airway obstruction. A brief discussion of the application of imaging in the child with sleep apnea is included.