Mild Manifestations Research Articles

Paromomycin is superior to metronidazole in Dientamoeba fragilis treatment

Dientamoeba fragilis is a trichomonad parasite of the human intestine that is found worldwide. However, the biological cycle and transmission of this parasite have yet to be elucidated. Although its pathogenic capacity has been questioned, there is increasing evidence that clinical manifestations vary greatly. Different therapeutic options with antiparasitic drugs are currently available; however, very few studies have compared the effectiveness of these drugs. In the present longitudinal study, we evaluate 13,983 copro-parasitological studies using light microscopy of stools, during 2013–2015, in Terrassa, Barcelona (Spain). A total of 1150 (8.2%) presented D. fragilis. Of these, 739 episodes were finally analyzed: those that involved a follow-up parasitology test up to 3 months later, corresponding to 586 patients with gastrointestinal symptoms (53% under 15 years of age). Coinfection by Blastocystis hominis was present in 33.6% of the subjects. Our aim was to compare therapeutic responses to different antiparasitic drugs and the factors associated with the persistence of D. fragilis post-treatment. Gender, age, and other intestinal parasitic coinfections were not associated with parasite persistence following treatment. Metronidazole was the therapeutic option in most cases, followed by paromomycin: 65.4% and 17.5% respectively. Paromomycin was found to be more effective at eradicating parasitic infection than metronidazole (81.8% vs. 65.4%; p = 0.007), except in children under six years of age (p = 0.538). Although Dientamoeba fragilis mainly produces mild clinical manifestations, the high burden of infection means we require better understanding of its epidemiological cycle and pathogenicity, as well as adequate therapeutic guidelines in order to adapt medical care and policies to respond to this health problem.

The citrus flavonoid naringenin impairs the in vitro infection of human cells by Zika virus

The Zika virus (ZIKV) is an arthropod-borne virus that belongs to the Flaviviridae family. The ZIKV infection is usually asymptomatic or is associated with mild clinical manifestations; however, increased numbers of cases of microcephaly and birth defects have been recently reported. To date, neither a vaccine nor an antiviral treatment has become available to control ZIKV replication. Among the natural compounds recognized for their medical properties, flavonoids, which can be found in fruits and vegetables, have been found to possess biological activity against a variety of viruses. Here, we demonstrate that the citrus flavanone naringenin (NAR) prevented ZIKV infection in human A549 cells in a concentration-dependent and ZIKV-lineage independent manner. NAR antiviral activity was also observed when primary human monocyte-derived dendritic cells were infected by ZIKV. NAR displayed its antiviral activity when the cells were treated after infection, suggesting that NAR acts on the viral replication or assembly of viral particles. Moreover, a molecular docking analysis suggests a potential interaction between NAR and the protease domain of the NS2B-NS3 protein of ZIKV which could explain the anti-ZIKV activity of NAR. Finally, the results support the potential of NAR as a suitable candidate molecule for developing anti-ZIKV treatments.

Possibilities of Combination of Beta-blockers and Ivabradine in Patients with Stable Angina Pectoris

Aim. To evaluate the therapeutic efficacy of a combination of ivabradine and beta-blockers (BAB) in patients with stable angina, initially taking only BAB and not reaching the target heart rate (HR) due to the risk of hypotension.Material and methods. A prospective observational post-registration study was performed at the Research Institute for Complex Issues of Cardiovascular Diseases. The study included 50 patients with stable angina pectoris (diagnosed by coronary angiography in combination with clinical manifestations of angina of functional class II-III according to the Canadian classification) and an initial sinus rhythm with a heart rate of more than 70 beats per minute. These patients have already taken BAB. Heart rate, the number of angina attacks, nitrate intake and quality of life indicators according to the questionnaire were evaluated as criteria for therapeutic efficacy.Results. Taking the study drug in combination with BAB led to a significant decrease the average heart rate at rest by 20%, as well as after a six-minute walk test (TLC) in most patients (p<0.050), and a decrease in the total number of angina attacks per week from 5 to less than 1 (p<0.050) and the frequency of nitrate intake for the relief of angina attacks from 58% to 20% (p=0.001). Therapy with ivabradine (Bravadin) was well tolerated by patients: there were no adverse events in the observed sample of patients, patients had a high adherence to treatment (100% of the contents of handed out blisters were used). During the 3 months of follow-up, according to the EQ-5D-5L quality of life questionnaire, patients improved their perception of their own health level (p<0.050), the number of patients experiencing mild (p=0.034) and strong (p=0.041) mobility limitations decreased; strong (p=0.024) restriction in self-care, mild (p=0.041) and strong (p=0.024) restriction of daily activities, mild manifestation of pain (p=0.009) and mild anxiety (p=0.027) also were reduced compared with the initial questionnaires.Conclusion. Ivabradine (Bravadin) in addition to BAB is an effective and safe antianginal therapy for the prevention of angina attacks by reducing the initially high heart rate in patients with angina pectoris of functional class II-III.

Experimental challenge with bovine respiratory syncytial virus in dairy calves: bronchial lymph node transcriptome response

Bovine Respiratory Disease (BRD) is the leading cause of mortality in calves. The objective of this study was to examine the response of the host’s bronchial lymph node transcriptome to Bovine Respiratory Syncytial Virus (BRSV) in a controlled viral challenge. Holstein-Friesian calves were either inoculated with virus (103.5 TCID50/ml × 15 ml) (n = 12) or mock challenged with phosphate buffered saline (n = 6). Clinical signs were scored daily and blood was collected for haematology counts, until euthanasia at day 7 post-challenge. RNA was extracted and sequenced (75 bp paired-end) from bronchial lymph nodes. Sequence reads were aligned to the UMD3.1 bovine reference genome and differential gene expression analysis was performed using EdgeR. There was a clear separation between BRSV challenged and control calves based on gene expression changes, despite an observed mild clinical manifestation of the disease. Therefore, measuring host gene expression levels may be beneficial for the diagnosis of subclinical BRD. There were 934 differentially expressed genes (DEG) (p < 0.05, FDR <0.1, fold change >2) between the BRSV challenged and control calves. Over-represented gene ontology terms, pathways and molecular functions, among the DEG, were associated with immune responses. The top enriched pathways included interferon signaling, granzyme B signaling and pathogen pattern recognition receptors, which are responsible for the cytotoxic responses necessary to eliminate the virus.

CT FOR EARLY DIAGNOSIS OF SPUTUM-SMEAR NEGATIVE PULMONARY TB IN ENDEMIC POPULATIONS

SESSION TITLE: Monday Fellow Case Report Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: Early diagnosis of Tuberculosis (TB) is critical for prompt treatment and diagnostic dilemmas can delay appropriate treatment. We review 2 cases of sputum smear-negative pulmonary TB (SSN-pTB). CASE PRESENTATION: Case 1. A 57 year old Chinese man presented with haemoptysis. Radiology revealed a papillary thyroid carcinoma with severe extrinsic tracheal compression and infiltration. He received a total thyroidectomy. Although initial smear and molecular tests were negative on sputum, empiric TB treatment was started given tree-in-bud changes in the right upper lobe on CT. TB cultures from sputum and tracheal aspirates proved TB infection 6 weeks later. Case 2. A 34 year old Filipino pregnant lady presented with haemoptysis and near syncope. Ultrasound of calves were negative for deep venous thrombosis while CT pulmonary angiography revealed only left upper lobe tree in bud changes. Subsequent sputum studies were smear negative but molecular positive TB with culture conversion 2 months later. She was initiated on TB treatment with good outcomes. DISCUSSION: The diagnosis of pTB depends on clinical features and the decision to initiate treatment depends on the pre-test probability. Patients with sputum smear-negative pTB (SSN-pTB) pose as diagnostic dilemmas as they usually have mild symptoms or systemic manifestations. Culture conversion often requires 6-8 weeks to confirm the diagnosis hence losing valuable time for effective and early treatment. Although sputum TB smear and culture are the gold standards in diagnosing pTB, patients may not have sputum. While flexible fiberoptic bronchoscopy can increase the diagnostic yield of SSN-pTB this is invasive and bear risks of complications arising from anticipated difficult airways in both patients. Although empiric TB treatment can be initiated in younger patients with minimal adverse reactions as with the first patient, this cannot be similarly applied to the second patient given clear obstetric and gynaecological considerations to initiating TB treatment without diagnostic confirmation. Confirmation of pTB before initiating treatment is still ideal in either case. CT can be useful in the rapid diagnosis of pTB. Tree-in-bud appearance is the most significant association with active PTB in 24-33% of patients[1] with SSN-pTB. CT features suggestive of pTB reportedly have high sensitivity, specificity as well as positive- and negative- predictive values[2]. In particular, HRCT has been shown to predict the risk of PTB with good reproducibility [3]and is a good diagnostic tool to identify patients with high risk of pTB. CONCLUSIONS: It is important to consider and screen for TB in high risk patients especially if early diagnosis and subsequent treatment of TB is necessary. Tree-in-bud appearance on CT is highly suggestive of PTB in an endemic population and can be useful in the diagnosis of patients with SSN-pTB with difficulty expectorating sputum. Reference #1: Hatipoglu et al . Thorax 1996: 51: 397-402 Reference #2: JS park et al ERJ 2016 48 (60): PA3806 Reference #3: Nakanishi M et al. Eur J Radiol. 2010 Mar;73(3):545-50 DISCLOSURES: no disclosure on file for Kay See; No relevant relationships by Genevieve Tan, source=Web Response

Removal of a Missing Intrauterine Device Via Laparotomy after 28 Years of Insertion: A Case Report

Intrauterine device is one of the most preferred contraceptive methods. Rare complications such as uterine perforation were getting more common due to increased use of intrauterine device and could be seen either with mild manifestations or serious cases like bladder or intestinal damage. A 48-year-old patient who is consulted to our clinic because of a missed copper intrauterine device was presented. The intrauterine device was inserted 28 years ago, detected in pelvis incidentally by x-ray and extracted via laparotomy. Although device has been in abdomen for nearly three decades, we did not see any serious reaction or adhesion during surgery.Management of a patient with intrauterine device should be done carefully and following the instructions before insertion, regular examination at every visit are important.

Novel pathogenic TGFBR1 and SMAD3 variants identified after cerebrovascular events in adult patients with Loeys-dietz syndrome

IntroductionLoeys-Dietz syndrome (LDS) is an autosomal dominant connective tissue disorder due to heterozygous pathogenic variants in transforming growth factor beta (TGFβ) signaling-related genes. LDS types 1–6 are distinguished depending on the involved gene. LDS is characterized by multiple arterial aneurysms and dissections in addition to variable neurological and systemic manifestations.Patient 1: a 68-year-old man was admitted due to an aphasic transient ischemic attack (TIA). Brain CT-scan and CT angiography revealed a chronic and asymptomatic right vertebral artery dissection. Stroke diagnostic panel was unremarkable. His history showed mild stroke familiarity. At age of 49, he was treated for dissecting-aneurysm of the ascending aorta and started anticoagulation therapy. Seven years later, he underwent surgery for dissecting aneurysm involving aortic arch, descending-thoracic aorta, left subclavian artery, and both iliac arteries. Patient 2: a 47-year-old man presented a left hemiparesis due to right middle cerebral artery (MCA) and anterior cerebral artery (ACA) occlusion caused by right internal carotid artery (ICA) dissection after sport activity. Despite i.v. thrombolysis and mechanical thrombectomy, he developed malignant cerebral infarction and underwent decompressive hemicraniectomy. Digital subtraction angiography showed bilateral carotid and vertebral kinking, aneurysmatic dilatation on both common iliac arteries and proximal ectasia of the descending aorta. His father and his uncle died because of an ischemic stroke and a cerebral aneurysm rupture with a subarachnoid hemorrhage (SAH), respectively. Discussionin both cases, considering the family history and the multiple dissections and aneurysms, LDS molecular analysis was performed. In patient 1, the novel NM_005902.3 (SMAD3): c.840T > G; p.(Asn280Lys) likely pathogenic variant was identified, thus leading to a diagnosis of LDS type 3. In patient 2, the novel NM_004612.2 (TGFBR1): c.1225T > G; p.(Trp409Gly) likely pathogenic variant was found, allowing for a diagnosis of LDS type 1. ConclusionLDS is characterized by genetic and clinical variability. Our report suggests that this genetically-determined connective tissue disorder is probably underestimated, as it might firstly show up with cerebrovascular events, although mild systemic manifestations. These findings could lead to identify people at risk of severe vascular complications (i.e., through genetic consult on asymptomatic relatives), in order to perform adequate vascular assessments and follow-up to prevent complications such as stroke.

PERIPHERAL NEUROPATHY IN BEHÇET'S DISEASE: CLINICAL AND NEUROPHYSIOLOGICAL STUDY

Background: Behcet’s disease (BD) is a chronic idiopathic relapsing condition, whereas multiple organs are affected as a sequential effect of the vascular and inflammatory process. Based on the neurophysiological studies, 20-40% of BD patients may have silent neurological involvement (SNI) with no or very mild clinical manifestations. Objectives: Assessing clinically and electro physiologically the prevalence of symptomatic and asymptomatic peripheral neuropathy (PN) among BD patients along with the potential predictors of PN among BD patients. Patients and Methods: All patients with clinically established BD according to the International Criteria for Behcet's Disease (ICBD) were involved in the current study. All patients were submitted to clinical evaluation, neuropathy symptom score (NSS) along with electrophysiological nerve conduction studies including sensory and motor nerve conduction assessment. Results: An overall 30 participants who fulfilled the inclusion criteria were enrolled in the study. There were 22 (73.3%) males and 8 (26.7%) females with a mean age of 37.9±8.31 years. Based on the electrophysiological studies, 16 (53.3%) patients had the evidence of peripheral neuropathy in the terms of mixed (23.3%), motor (6.6%), and sensory (23.3%) nerve affection. The most affected peripheral nerve was sural nerve (46.6%) succeeded by peroneal (43.3%) and ulnar (20%) nerves. The univariate regression model showed that the age of the patients and the duration of the disease were independent predictors of peripheral neuropathy. Conclusion: PN is a considerable complication of BD, whereby health care providers should employ a routine follow up protocol for early detection of even the subclinical PN.

PERIPHERAL NEUROPATHY IN BEHÇET'S DISEASE: CLINICAL AND NEUROPHYSIOLOGICAL STUDY

Background: Behcet’s disease (BD) is a chronic idiopathic relapsing condition, whereas multiple organs are affected as a sequential effect of the vascular and inflammatory process. Based on the neurophysiological studies, 20-40% of BD patients may have silent neurological involvement (SNI) with no or very mild clinical manifestations. Objectives: Assessing clinically and electro physiologically the prevalence of symptomatic and asymptomatic peripheral neuropathy (PN) among BD patients along with the potential predictors of PN among BD patients. Patients and Methods: All patients with clinically established BD according to the International Criteria for Behcet's Disease (ICBD) were involved in the current study. All patients were submitted to clinical evaluation, neuropathy symptom score (NSS) along with electrophysiological nerve conduction studies including sensory and motor nerve conduction assessment. Results: An overall 30 participants who fulfilled the inclusion criteria were enrolled in the study. There were 22 (73.3%) males and 8 (26.7%) females with a mean age of 37.9±8.31 years. Based on the electrophysiological studies, 16 (53.3%) patients had the evidence of peripheral neuropathy in the terms of mixed (23.3%), motor (6.6%), and sensory (23.3%) nerve affection. The most affected peripheral nerve was sural nerve (46.6%) succeeded by peroneal (43.3%) and ulnar (20%) nerves. The univariate regression model showed that the age of the patients and the duration of the disease were independent predictors of peripheral neuropathy. Conclusion: PN is a considerable complication of BD, whereby health care providers should employ a routine follow up protocol for early detection of even the subclinical PN.

Clinicopathological analysis for IgA nephropathy with isolated hematuria and/or mild proteinuria

To investigate the correlation of different types of urinary abnormalities or different proteinuria and hematuria with the pathological injury of kidney in IgA nephropathy with isolated hematuria and/or mild proteinuria. Methods: Patients with primary IgA nephropathy, isolated hematuria and/or mild proteinuria were enrolled in the Department of Nephrology, the Second Xiangya Hospital, Central South University from January 2013 to January 2018. According to the difference of red blood cell count in urinary sediment and quantitative of 24-hour urinary protein (24 h-UP) during renal biopsy, the patients were grouped in 3 ways: a simple hematuria group, a hematuria and proteinuria group, and a simple proteinuria group; a proteinuria I group, a proteinuria II group, and a proteinuria III group; a hematuria I group, a hematuria II group, and a hematuria III group. The clinical parameters such as age, mean arterial pressure, blood urea nitrogen, serum creatinine, blood uric acid, 24 h-UP, and renal pathological damage were compared. Results: A total of 157 patients met the inclusion criteria, including 71 males and 86 females. The most common pathological type was focal and/or segmental glomerulosclerosis. The Lee's classification were dominated by grade III and IV, and the renal pathological injury was heavy. Immunoglobulin deposition was dominated by simple IgA deposition. The most common fluorescence intensity of IgA deposition was +++. 97 (61.78%) patients were accompanied by complement deposition and were mainly composed of simple complement C3 deposition. There were 18 patients (11.47%) in the simple hematuria group, 111 patients (70.70%) in the hematuria and proteinuria group, and 28 patients (17.83%) in the simple proteinuria group. Compared with the simple hematuria group, the proportion of patients with mild injury was lower in the simple proteinuria group, and the proportion of patients with moderate-to-severe injuries was increased (χ2=7.053, P=0.008). Compared with the hematuria and proteinuria group, the proportion of patients with mild injury was lower in the simple proteinuria group, and the proportion of patients with moderate-to-severe injury was increased (χ2=4.294, P=0.038). Compared with the proteinuria I group, the proportion of patients with mild injury was lower in the proteinuria III group, and the proportion of patients with moderate-to-severe injury was increased (χ2=5.433, P=0.020). There was no significant difference in the proportion of patients with renal pathological injury among different hematuria groups (P>0.05). Conclusion: The clinical manifestations of patients with IgA nephropathy with hematuria and/or mild proteinuria are inconsistent with renal pathological damage. Some patients with mild clinical manifestations have severe renal pathological damage and the renal pathological damage is more serious in simple proteinuria. The more proteinuria, the heavier the renal pathological damage.

NGS-based targeted resequencing identified rare subtypes of albinism: Providing accurate molecular diagnosis for Japanese patients with albinism.

Albinism, which is commonly inherited as an autosomal recessive trait, is characterized by a reduction or absence of melanin in the eyes, skin, and hair. To date, more than 20 causal genes for albinism have been identified; thus, the accurate diagnosis of albinism requires next-generation sequencing (NGS). In this study, we analyzed 46 patients who tested negative for oculocutaneous albinism (OCA)1-4 and Hermansky-Pudlak syndrome (HPS)1 based on conventional analysis, in addition to 28 new Japanese patients, using NGS-based targeted resequencing. We identified a genetic background for albinism in 18 of the 46 patients (39%), who were previously tested negative according to the conventional analysis. In addition, we unveiled a genetic predisposition toward albinism in 23 of the 28 new patients (82%). We identified six patients with rare subtypes of albinism, including HPS3, HPS4, and HPS6, and found 12 novel pathological mutations in albinism-related genes. Furthermore, most patients who were not diagnosed with albinism by the NGS analysis showed mild manifestations of albinism without apparent eye symptoms and harbored only one heterozygous mutation, occasionally in combination with skin-color associated gene variants.

Novel EXOSC3 pathogenic variant results in a mild course of neurologic disease with cerebellum involvement

EXOSC3-related autosomal recessive neurodevelopmental disorders are rare entities with variable clinical course and prognosis. They are characterized by hypoplasia of cerebellar structures and pons, degeneration of the anterior horn cells and motor as well as neurocognitive impairment. Phenotypic expression is variable with an overall poor outcome. Current research suggests clear genotype-phenotype correlations among EXOSC3-pathogenic-variants carriers. Homozygosity for the EXOSC3 variant c.395A > C, p.(Asp132Ala) is proposed to lead to a rather mild phenotype compared to compound-heterozygous EXOSC3-pathogenic-variants carriers with lethal neurological disease in very early childhood. In this study, we report two siblings (21- and 8-year-old) affected by PCH1B with an unusual presentation. We identified compound heterozygosity for the well-established EXOSC3 variant c.395A > C, p.(Asp132Ala) and the novel variant c.572G > A, p.(Gly191Asp), expanding the genetic spectrum. Phenotypic presentation of the siblings was strikingly different from that of literature reports with a surprisingly mild disease manifestation and an unexpected intrafamilial variability. This study demonstrates the extensive clinical heterogeneity and the broad phenotypic spectrum associated with EXOSC3-associated disorders. Enlargement of sample sizes and reports of novel cases will be essential for the delineation of associated phenotypes.

Virulence evaluation of classical swine fever virus subgenotype 2.1 and 2.2 isolates circulating in China

Classical swine fever (CSF) remains an important pig disease in China, where it usually presents with mild or atypical clinical manifestations, with large scale outbreaks rarely seen. This has led to speculation about the possible circulation of viral strains of low virulence. To investigate this possibility, five field isolates within the predominant genotype 2 (2.1b, 2.1c, 2.1 h and 2.2) were evaluated and compared by experimental infection of naturally farrowed but colostrum-deprived piglets. All infected piglets displayed clinical signs, including persistent high fever, depression, anorexia, dyspnea, conjunctivitis, constipation, and hesitant gait. Typical pathological lesions, including pulmonary edema, hemorrhagic or cellulosic exudation, and swelling and hemorrhage of lymph nodes, were observed. Viremia and Erns protein expression in the blood of all infected animals were detectable from 3 to 5 days post infection (DPI), their presence correlating with the onset of fever, clinical signs and leukopenia. E2 antibody did not develop in any of the field CSFV-infected piglets during the disease course, while Erns antibody was detectable in 4–56% of infected animals at various time points. Mortalities ranged from 20 to 80% within 21 DPI, progressing to 100% by 43 DPI. Based on clinical scores and fatalities within 21 DPI, 2 of the 5 field isolates were classified as of moderate virulence and 3 of high virulence; i.e., no field isolates of low virulence were identified. The study has provided data supporting the use of these isolates as challenge viruses to evaluate the efficacy of current CSF vaccines.

Vector-borne transmission and evolution of Zika virus.

Zika virus (ZIKV), discovered in the Zika Forest of Uganda in 1947, is a mosquito-borne flavivirus related to yellow fever, dengue and West Nile viruses. From its discovery until 2007, only sporadic ZIKV cases were reported, with mild clinical manifestations in patients. Therefore, little attention was given to this virus before epidemics in the South Pacific and the Americas that began in 2013. Despite a growing number of ZIKV studies in the past three years, many aspects of the virus remain poorly characterized, particularly the spectrum of species involved in its transmission cycles. Here, we review the mosquito and vertebrate host species potentially involved in ZIKV vector-borne transmission worldwide. We also provide an evidence-supported analysis regarding the possibility of ZIKV spillback from an urban cycle to a zoonotic cycle outside Africa, and we review hypotheses regarding recent emergence and evolution of ZIKV. Finally, we identify critical remaining gaps in the current knowledge of ZIKV vector-borne transmission.

Dynamics of quality of dream and cognitive functions for the patients of young age with primary insomnia on background the reception of Sonmelat forte

The aim of the study was to assess the quality of sleep, cognitive functions and the effect of insomnia on work and social adaptation in young patients suffering from primary insomnia (in accordance with the DSM-5 and ICD-10 criteria for insomnia) and their dynamics under the influence of Sonmelate forte.Materials and methods. The study involved 23 patients (mean age – 41,3±2,8 years) with chronic primary insomnia and a duration of insomnia disorders of 7,79±2,4 months. The control group consisted of 20 healthy individuals (mean age 40,6±2,3 years) with no insomnia. In order to treat insomnia, patients took Sonmelate Forte (combination of 5 mg of melatonin immediate and 5 mg of melatonin sustained release) 1 tablet 30 minutes before sleep for 30 days.Results of the study. Chronic primary insomnia in young patients contributes to the development of mild manifestations of cognitive dysfunction in the form of impaired short-term visual and auditory memory, decreased concentration, stability and increased attention depletion, and also contributes to the development of emotional disturbances (anxiety, depression), work and socialmaladjustment. Sonmelat Forte is an effective and safe means of treating chronic primary insomnia in young patients, helping to reduce sleep latency, night and early awakenings, increase night sleep duration and decrease daytime sleepiness, promotes regression of mild cognitive dysfunction in young patients (improvement in short-term visual and auditory memory, attention span), improves the patient’s emotional state and daytime functioning by decreasing daytime oh sleepiness and general fatigue, contributing, thus, to increase the level of social and work adaptation.

Variable response to low-dose naltrexone in patients with Darier disease: a case series.

Darier disease is a rare autosomal-dominant genodermatosis with a loss of function of a Ca2+ -ATPase pump (SERCA2-pump). Clinically, the disease is characterized by red-brown keratotic papules mainly in seborrhoeic areas and has only limited and unsatisfactory treatment options. Previously, low-dose naltrexone was described as a successful treatment option in Hailey-Hailey disease, a genodermatosis with a genetic mutation coding for a similar loss of function of a Ca2+ -ATPase pump (hSPCA1-pump). To assess the efficacy of low-dose naltrexone as a treatment option in Darier disease. Six patients with biopsy-proven Darier disease (four had severe, one had moderate and one mild clinical manifestations). The patients received off-label therapy with naltrexone [5mg per os (p.o.)] and magnesium [200mg p.o.]. Patients were followed up every 4weeks for minimally 12weeks. Upon clinical presentation, the disease severity and subjective pain and itch scores were assessed, and standardized photographs were obtained. The clinical response to naltrexone varied after 12weeks. The four patients with severe Darier disease showed worsening after initial improvement during the first 4weeks, whereas the two patients with a mild to moderate clinical manifestation clearly improved, showing almost full remission after 12weeks with complete flattening of the keratotic papules. Low-dose naltrexone did not have an effect on severe Darier disease compared to Hailey-Hailey disease, but it was beneficial in mild to moderate forms of the disease. Further studies are needed to confirm these observations of variable responses.

Application of next generation sequencing for the elucidation of genes and pathways involved in the host response to bovine respiratory syncytial virus

High rates of calf mortality in the first 12 months of life, results in significant economic losses in Europe and the USA. Bovine respiratory disease (BRD) accounts for the largest proportion of calf mortality. There is a paucity of literature concerning the host response to BRD. In a controlled challenge study in artificially reared dairy calves [155 (S.D. 14) kg], the influence of the host response to bovine respiratory syncytial virus (BRSV) was examined. At AFBI Holstein-Friesian calves were either challenged with BRSV (n=12) or mock challenged with phosphate buffer saline (n=6). Calves were euthanised on day 7 post-challenge. Bronchial lymph nodes were collected and flash-frozen at −80 °C. RNA was extracted and sent to the University of Missouri’s DNA Core Facility for RNA-Seq library preparation and sequencing. Sequenced reads were adapter trimmed, quality assessed using FastQC and aligned to the bovine genome (UMD 3.1) using STAR. Differential gene expression analysis was performed using EdgeR, and pathway and gene ontology analyses were carried out using g:Profiler and Ingenuity Pathway Analysis (IPA). There was a clear separation between BRSV challenged and control calves based on log2 fold gene expression changes, despite an observed mild clinical manifestation of the disease. There were 934 differentially expressed genes (DEG) (P&lt;0.05, FDR&lt;0.1, fold change &gt;2) between the BRSV challenged and control calves. Over-represented pathways and gene ontology terms among the DEG were associated with immune responses and included: GO:0051607 defense response to virus, the KEGG pathway Influenza A and the IPA pathway Interferon Signaling.

Panniculitis in childhood-onset systemic lupus erythematosus: a multicentric cohort study

ObjectiveTo evaluate prevalence, clinical manifestations, laboratory abnormalities, treatment and outcome in a multicenter cohort of childhood-onset systemic lupus erythematosus (cSLE) patients with and without panniculitis.MethodsPanniculitis was diagnosed due to painful subcutaneous nodules and/or plaques in deep dermis/subcutaneous tissues and lobular/mixed panniculitis with lymphocytic lobular inflammatory infiltrate in skin biopsy. Statistical analysis was performed using Bonferroni correction(p < 0.004).ResultsPanniculitis was observed in 6/847(0.7%) cSLE. Painful subcutaneous erythematosus and indurated nodules were observed in 6/6 panniculitis patients and painful subcutaneous plaques in 4/6. Generalized distribution was evidenced in 3/6 and localized in upper limbs in 2/6 and face in 1/6. Cutaneous hyperpigmentation and/or cutaneous atrophy occurred in 5/6. Histopathology features showed lobular panniculitis without vasculitis in 5/6(one of them had concomitant obliterative vasculopathy due to antiphospholipid syndrome) and panniculitis with vasculitis in 1/6. Comparison between cSLE with panniculitis and 60 cSLE without panniculitis with same disease duration [2.75(0–11.4) vs. 2.83(0–11.8) years,p = 0.297], showed higher frequencies of constitutional involvement (67% vs. 10%,p = 0.003) and leukopenia (67% vs. 7%,p = 0.002). Cutaneous atrophy and hyperpigmentation occurred in 83% of patients.ConclusionsPanniculitis is a rare skin manifestation of cSLE occurring in the first three years of disease with considerable sequelae. The majority of patients have concomitant mild lupus manifestations.

Mental constitution and mental disease: from Th. Tilings's to E. Kretschmer's concepts

The dynamics of the concept of the continual development of mental disease from the constitution that was the most clearly formulated by a Russian psychiatrist Th. Tiling in the discussion with the German psychiatrist C. Neisser is presented. The concept of Th. Tiling influenced E. Bleuler's approach to the description of basic and accessory symptoms of schizophrenia and also on E. Kretschmer's concept of constitution and mental disease. Main characteristics of cycloid and schizoid personality of E. Kretschmer's concept are presented. The author notes the very broad E. Kretschmer's understanding of 'psychesthetic proportion', which state explains not only the diversity of schizoid types but also many psychotic psychopathological phenomena. In addition to the altered affectivity, autism was the second basic symptom of schizophrenia, which mild manifestations form the basis for E. Kretschmer systematics of schizoid types. E. Kretschmer's understanding of autism was broader than Bleuler's and was presented by E. Kretschmer as a symptom derived from special schizoid affectivity (psychesthetic proportion). The critics of E. Kretschmer's concept by some contemporary German psychiatrists is also considered.

Inflammatory and Infectious Syndromes Associated With Cancer Immunotherapies.

Immunotherapy using antibodies to immune checkpoint molecules or targeted chimeric antigen receptor-modified T cells (CAR-T cells) represent dramatic advances in cancer treatment. These therapies mediate immune-related adverse events that may mimic or amplify infectious presentations. Checkpoint inhibitor therapy may be associated with diverse irAEs including mild skin, endocrine, and autoimmune manifestations or severe inflammatory processes including colitis, pneumonitis, myocarditis, and shock. CAR-T-cell therapies may induce toxicities including cytokine-release syndrome with fevers and multiorgan dysfunction, CAR-T-cell-related encephalopathy syndrome with altered mental status and neurologic dysfunction, or hemophagocytic lymphohistiocytosis-macrophage-activation syndrome. Infectious risks may relate to prior cancer therapies or to treatments of inflammatory dysregulation, including corticosteroids and inhibitors of tumor necrosis factor-α and interleukin-6. Immune activation may unmask subclinical infections. Clinical approaches must attempt to identify infections in the face of immunotherapy-associated inflammatory processes. Empirical antimicrobial therapies should not be delayed based on the presumption of noninfectious syndromes.