Lessons from Dairy Farmers for Occupational Allergy and Respiratory Disease.

PURPOSE OF REVIEW: Exposure to bioaerosols at dairies has long been associated with allergy, respiratory disease, and decreases in lung function. Recent advancements in exposure assessments have aided our understanding on the size distribution and composition of these bioaerosols, but investigations focusing solely on exposures may overlook important intrinsic factors impacting worker's susceptibility to disease. RECENT FINDINGS: In our review, we discuss the most recent studies examining the exposures and genetic factors that contribute to occupational disease in dairy work. We also review more recent concerns in livestock work associated with zoonotic pathogens, antimicrobial resistant genes, and the role of the human microbiome. The studies highlighted in this review demonstrate the need for further research to better understand bioaerosol exposure-response relationships in the context of extrinsic and intrinsic factors, antibiotic-resistant genes, viral pathogens, and the human microbiome to help inform effective interventions that improve respiratory health among dairy farmers.

Skin resident memory CD8+ T cells are phenotypically and functionally distinct from circulating populations and lack immediate cytotoxic function.

The in-depth understanding of skin resident memory CD8+ T lymphocytes (TRM ) may help to uncover strategies for their manipulation during disease. We investigated isolated TRM from healthy human skin, which expressed the residence marker CD69, and compared them to circulating CD8+ T cell populations from the same donors. There were significantly increased proportions of CD8+ CD45RA- CD27- T cells in the skin that expressed low levels of killer cell lectin-like receptor G1 (KLRG1), CD57, perforin and granzyme B. The CD8+ TRM in skin were therefore phenotypically distinct from circulating CD8+ CD45RA- CD27- T cells that expressed high levels of all these molecules. Nevertheless, the activation of CD8+ TRM with T cell receptor (TCR)/CD28 or interleukin (IL)-2 or IL-15 in vitro induced the expression of granzyme B. Blocking signalling through the inhibitory receptor programmed cell death 1 (PD)-1 further boosted granzyme B expression. A unique feature of some CD8+ TRM cells was their ability to secrete high levels of tumour necrosis factor (TNF)-α and IL-2, a cytokine combination that was not seen frequently in circulating CD8+ T cells. The cutaneous CD8+ TRM are therefore diverse, and appear to be phenotypically and functionally distinct from circulating cells. Indeed, the surface receptors used to distinguish differentiation stages of blood T cells cannot be applied to T cells in the skin. Furthermore, the function of cutaneous TRM appears to be stringently controlled by environmental signals in situ.

Routine screening for colonization by Gram-negative bacteria in neonates at intensive care units for the prediction of sepsis: systematic review and meta-analysis.

BACKGROUND: At neonatal intensive care units, sepsis due to Gram-negative bacteria is an important cause of morbidity and mortality. The benefits of routine microbiological screening of neonatal body surface to predict and prevent sepsis are controversial. AIM: To evaluate the prognostic value of neonatal body surface screening for colonization with Gram-negative bacteria for the prediction of late-onset sepsis. METHODS: A systematic review was performed, including studies of any design that reported data to calculate prognostic accuracy of surface screening for the prediction of late-onset sepsis. Risk of bias was assessed and a meta-analysis performed. Evidence quality was appraised using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. FINDINGS: Eight studies (all cohort design) were identified as eligible. Studies were performed in six countries in Europe, Asia, and North America and comprised a total of 4829 participants. All studies were at high risk of bias. Pooled sensitivity of body surface screening to predict late-onset sepsis was 41% (95% confidence interval: 17-70), whereas pooled specificity was 56% (34-76) (hierarchical summary receiver operating characteristics (HSROC) model). Subgroup analyses showed higher pooled estimates for specificity but not sensitivity when screening focused on Escherichia coli or Klebsiella pneumoniae. GRADE evidence quality was very low. CONCLUSION: Limited evidence of very low quality exists regarding the prognostic value of neonatal screening for late-onset sepsis. Carefully planned and conducted prospective studies, including randomized trials, are needed to clarify the potential value of this measure for the prediction and prevention of late-onset sepsis.

Health-Related Behaviour Among Children of Childhood Cancer Survivors in Germany.

Purpose: Childhood cancer survivors fear that previous therapy could not only impair their own but also their children's health. We examined whether health-related behaviour in children of childhood cancer survivors differs from the general population. Methods: Our first nationwide survey wave (2013-2014) surveyed offspring health in 396 German childhood cancer survivors known to have a child of their own. Answers about health behaviour were analysed using descriptive statistics. Data were collected for 418 offspring and 394 could be integrated for matched-pair analyses with data from the German general population (KIGGS, n=17 641). Results: Teeth-cleaning routine, body-mass-index or subjective body image evaluation by parents were no different from children in the general population. Parents who included a cancer survivor smoked less in the presence of their children (p=0.01). During pregnancy, mothers in cancer survivor parent pairs abstained from drinking alcohol more often (p=0.01) and smoked less (p=0.05). While the calculated effect sizes (Phi) were generally low (0.135-0.247), children from cancer survivors played less outdoors than peers did (p=0.01). Boys participated in sports outside a club more often (p=0.05) and watched less TV on weekdays (p=0.01) and girls spent more time on the computer during weekdays than peers did (p=0.01). Conclusions: This study provides the first data for health-related behaviour in cancer survivors' offspring and sheds light on differences to parenting in the general population. Multivariate analyses in a larger study population are needed to relate these differences to fear issues in cancer survivors.

Complication and local recurrence rate after endoscopic resection of large high-risk colorectal adenomas of ≥3 cm in size.

PURPOSE: Endoscopic resection is a widely used technique for treatment of large colorectal adenomas, but few data are available including only lesions larger than ≥2 cm. The aim of this study is to evaluate the complication and recurrence rate after endoscopic resection of high-risk colorectal adenomas ≥3 cm in size. METHODS: Retrospective analysis of a prospectively maintained database of patients undergoing polypectomy of large colorectal polyps of ≥3 cm. RESULTS: In 341 patients, 360 colorectal adenomas with a mean size of 3.9 cm were resected endoscopically. In 25 patients, a complication including 22 delayed bleedings (6.5%) and three perforations (0.9%) occurred. Single-variate analysis showed an increasing risk of complications for larger adenomas (3.9 vs. 4.6 cm; p ≤ 0.05). Two hundred twelve patients with 224 adenomas had undergone at least one documented follow-up endoscopy with a medium follow-up period of 16 months. In 95 resected lesions (42.4%), a residual adenoma occurred in the first follow-up colonoscopy (n = 88, 92.6%) or a recurrent adenoma occurred after at least one negative follow-up colonoscopy (n = 7, 7.4%). In multivariate analysis, risk factors were lesion size, sessile growth pattern, and the performing endoscopist. The complication and recurrence rate correlated inversely between endoscopists. CONCLUSIONS: The present study is the largest study showing complication and recurrence rates after colorectal polypectomy of advanced colorectal adenomas of ≥3 cm in size. Polyp size was identified as the most important risk factor for complications. For the first time, this study shows that the complication rate after colorectal polypectomy of large adenomas is correlated inversely with the residual and/or recurrence rate.

Animal model of metastatic pheochromocytoma: evaluation by MRI and PET.

OBJECTIVE: The development of metastatic pheochromocytoma animal model provides a unique opportunity to study the physiology of these rare tumors and to evaluate experimental treatments. Here, we describe the use of small animal imaging techniques to detect, localize and characterize metastatic lesions in nude mice. METHODS: Small animal positron emission tomography (PET) imaging and magnetic resonance imaging (MRI) were used to detect metastatic lesions in nude mice following intravenous injection of mouse pheochromocytoma cells. [18F]-6-fluoro-dopamine ([18F]-DA) and [18F]-L-6-fluoro-3,4-dihydroxyphenylalanine, which are commonly used for localization of pheochromocytoma lesions in clinical practice, were selected as radiotracers to monitor metastatic lesions by PET. RESULTS: MRI was able to detect liver lesions as small as 0.5mm in diameter. Small animal PET imaging using [18F]-DA and [18F]-DOPA detected liver, adrenal gland, and ovarian lesions. CONCLUSION: We conclude that MRI is a valuable technique for tumor growth monitoring from very early to late stages of tumor progression and that animal PET confirmed localization of metastatic pheochromocytoma in liver with both radiotracers.

[Juvenile laryngeal papillomatosis--immunisation with the polyvalent vaccine gardasil]. / Juvenile Larynxpapillomatose--Impfung mit dem polyvalenten Spaltimpfstoff Gardasil.

Juvenile laryngeal papillomatosis is a rare condition caused by human papilloma virus (HPV). In cases with rapid recurrences permanent impairments of voice and breathing are almost inevitable due to the frequent need of debulking surgeries. Efforts to lower the recurrence rate comprise the adjuvant use of interferon alpha, local cidofovir, photodynamic therapy or mumps vaccination. In the present case we tried to positively influence the aggressive course of disease in a two year old boy by immunisation with the quadrivalent HPV vaccine Gardasil(R). Chromogenic in-situ hybridisation analysis and polymerase chain reaction (PCR) of lesion tissue showed simultaneous infection with the HPV-Types 6 and 11. After the third immunisation the disease became stable. No further surgery was necessary for the last ten months. The risk profile of this adjuvant treatment is low. We think it worth to initiate a multicentre trial to prove a benefit of this treatment even if no complete virus elimination can be achieved.

Location and type of mutation in the LIS1 gene do not predict phenotypic severity.

BACKGROUND: Lissencephaly is a neuronal migration disorder leading to absent or reduced gyration and a broadened but poorly organized cortex. The most common form of lissencephaly is isolated, referred as classic or type 1 lissencephaly. Type 1 lissencephaly is mostly associated with a heterozygous deletion of the entire LIS1 gene, whereas intragenic heterozygous LIS1 mutations or hemizygous DCX mutations in males are less common. METHODS: Eighteen unrelated patients with type 1 lissencephaly were clinically and genetically assessed. In addition, patients with subcortical band heterotopia (n = 1) or lissencephaly with cerebellar hypoplasia (n = 2) were included. RESULTS: Fourteen new and seven previously described LIS1 mutations were identified. We observed nine truncating mutations (nonsense, n = 2; frameshift, n = 7), six splice site mutations, five missense mutations, and one in-frame deletion. Somatic mosaicism was assumed in three patients with partial subcortical band heterotopia in the occipital-parietal lobes or mild pachygyria. We report three mutations in exon 11, including a frameshift which extends the LIS1 protein, leading to type 1 lissencephaly and illustrating the functional importance of the WD domains at the C terminus. Furthermore, we present two patients with novel LIS1 mutations in exon 10 associated with lissencephaly with cerebellar hypoplasia type a. CONCLUSION: In contrast to previous reports, our data suggest that neither type nor position of intragenic mutations in the LIS1 gene allows an unambiguous prediction of the phenotypic severity. Furthermore, patients presenting with mild cerebral malformations such as subcortical band heterotopia or cerebellar hypoplasia should be considered for genetic analysis of the LIS1 gene.

[Staging of esophageal cancer using ultrasound]. / Staging des Osophaguskarzinoms mittels Ultraschall.

The early diagnosis of esophageal cancer is crucial for the prognosis of the disease. In contrast to cancer of the upper aerodigestive tract, the mucosa of the esophagus is not visible without the appropriate equipment. In addition to endoscopy, imaging of the esophagus is crucial for early detection of the esophageal cancer. Ultrasound of the esophagus can be performed easily and--in contrast to other imaging techniques--without side effects. Different modes of ultrasound can be performed. First, transcutaneous ultrasound allows one to detect tumors of the upper esophagus and its passage into the hypopharynx. Second, endosonography allows one to detect pathologies of the other esophageal regions including the passage into the stomach. The present review discusses the impact of both techniques against the background of the international literature.

[Gaucher disease, Fabry disease and mucopolysaccharidosis type I--how can the rheumatologist recognise these patients?]. / M. Gaucher, M. Fabry und Mukopolysaccharidose Typ I. Wie kann der Rheumatologe diese Patienten erkennen?

The lysosomal storage diseases Gaucher disease, Fabry disease and MPS I are rare inheritable metabolic disorders that are now treatable with enzyme replacement therapy. In order to avoid irreversible complications, an early diagnosis and initiation of therapy is important. Due to the musculoskeletal symptoms associated with these storage diseases, patients are likely to visit a rheumatologist, who should, therefore, be able to recognise and diagnose these rare diseases. On the basis of the causal factors behind Gaucher disease, Fabry disease und MPS I (here Scheie syndrome), key symptoms that the rheumatologist (internist or paediatrician) should be familiar with for the differential diagnosis of these patients will be discussed. In addition, a short introduction to the pathophysiology and data on the prognosis and therapy for these diseases will be presented.

Occult, life-threatening, cardial tumor in syndactylism in Gorlin Goltz syndrome.

Pediatric, orthopedic, plastic, and hand surgeons perform the surgical correction of syndactylism. It is sometimes forgotten, however, that syndactylism can be part of a syndrome. The components of such a syndrome can each be life threatening. A 7-month-old boy was hospitalized for correction of cutaneous syndactylism. The mother claimed that, with the exception of the syndactylism, her son was healthy. However, review of the admission documents found that the family physician suspected Gorlin Goltz syndrome. A preoperative echocardiography showed 3.9-cm intramural tumor in the wall of the left ventricle. Electrocardiography documented ventricular tachycardia. Because of the danger of life-threatening malignant ventricular tachycardia, the tumor was resected. Before the resection, cardiac transplantation was considered because of the size of the tumor. Histologic examination found a fibroma. When observing syndactylism, one must always be aware of the possibility of a syndromic disease. It is particularly important that screening investigations, including electrocardiography and echocardiography, are performed before surgical treatment.

Intracellular expression of pro-inflammatory cytokines (IL-1alpha, TNF-alpha, and IL-6) in chronic hepatitis C.

The study aimed at localizing TNF-alpha, IL-1alpha, IL-6 at light and electron microscope levels in patients with chronic hepatitis C, using the immunocytochemical techniques in biopsy material from patients with chronic hepatitis C and at comparing the expression of the cytokines with histopathological changes. Our studies demonstrated an augmented expression of all cytokines in liver biopsies in chronic hepatitis C, in comparison with respective values, obtained in control biopsy material. The highest expression of the cytokines was observed in hepatocytes. That was confirmed by electron microscopy, which demonstrated the cytokines mainly in altered ER cisterns and in the cytoplasm. In children, the expression of IL-1alpha was negatively correlated with staging, while in adult patients; the staging was positively correlated with the expression of TNF-alpha. The new element involves demonstration of cellular and subcellular expression of TNF-alpha, IL-1alpha and IL-6 in hepatocytes in in vivo infection.

Monitoring the correction of glycogen storage disease type 1a in a mouse model using [(18)F]FDG and a dedicated animal scanner.

Monitoring gene therapy of glycogen storage disease type 1a in a mouse model was achieved using [(18)F]FDG and a dedicated animal scanner. The G6Pase knockout (KO) mice were compared to the same mice after infusion with a recombinant adenovirus containing the murine G6Pase gene (Ad-mG6Pase). Serial images of the same mouse before and after therapy were obtained and compared with wild-type (WT) mice of the same strain to determine the uptake and retention of [(18)F]FDG in the liver. Image data were acquired from heart, blood pool and liver for twenty minutes after injection of [(18)F]FDG. The retention of [(18)F]FDG was lower for the WT mice compared to the KO mice. The mice treated with adenovirus-mediated gene therapy had retention similar to that found in age-matched WT mice. These studies show that FDG can be used to monitor the G6Pase concentration in liver of WT mice as compared to G6Pase KO mice. In these mice, gene therapy returned the liver function to that found in age matched WT controls as measured by the FDG kinetics in the liver compared to that found in age matched wild type controls.

PTHrP and cytokeratins in human epidermis.

We have demonstrated the presence of parathyroid hormone-related peptide (PTHrP) in cells of human epidermis, employing immunocytochemical techniques. Cells of human epidermal layers demonstrated variable intensity of the reaction. The least pronounced reaction was detected in cells of the basal and the most pronounced reaction in cells of the granular layer. Ultrastructural studies demonstrated that gold particles labeled bundles of keratin filaments. Therefore, at the subsequent stage of the studies we examined the type of filaments to which PTHrP was bound, using immunocytochemical reactions with antibodies against cytokeratins 10, 14, 16 and 19. Positive reaction was obtained for cytokeratins 10, 14 and 16. The reaction pattern obtained for cytokeratins 10 and 16 most closely resembled that of PTHrP. Double labeling with colloidal gold was performed at the ultrastructural level. The results obtained in this way demonstrated that PTHrP most probably binds to filaments built of cytokeratin 16. By binding to the cytokeratin, PTHrP may possibly affect growth and differentiation of keratinocytes.

Expression of mRNA for cytokines (TNF-alpha and IL-1alpha) in human cytomegalovirus (HCMV) and hepatitis B virus (HBV) infections.

The study was aimed at detecting cellular sources of transcripts for two cytokines, TNF-alpha and IL-1alpha in infection with human cytomegalovirus (HCMV) or hepatitis B virus (HBV). The studies were performed on paraffin sections of organs (liver, pancreas, spleen, lungs) obtained upon autopsy from a child deceased due to acute inborn HCMV infection, on paraffin sections of liver biopsy, obtained from a child with HCMV-induced chronic hepatitis, and of liver biopsies obtained from children with chronic type B hepatitis (n = 13). The classical in situ hybridization was applied with digoxygenin-labeled probes and amplification by the ImmunoMax technique. In HCMV infection, the most pronounced expression of mRNA for TNF-alpha and Il-1alpha was detected in pancreatic islets (mainly in beta cells) and, then, in a decreasing sequence, in liver (in macrophages and sinusoidal endothelial cells) and in lungs (in alveolar macrophages). No expression of the two cytokines was detected in the spleen. In HBV infection, weak expression of TNF-alpha and more intense expression of IL-1alpha in the liver were observed, mainly in sinusoidal endothelial cells and in macrophages as well as in hepatocytes. These results were confirmed by immunocytochemical experiments.

[Interdisciplinary treatment of early-onset ornithine transcarbamylase (OTC) deficiency. Two case reports and a review]. / Interdisziplinäre Behandlung des frühmanifesten Ornithintranscarbamylase(OTC)-Mangels1 - Zwei Patientenberichte und Literaturübersicht -

PATIENT REPORTS: We report on a male preterm infant (gestational age 31 weeks, birth weight 1420 g) and a male term infant (gestational age 38 weeks, birth weight 3680 g) with ornithine transcarbamylase (OTC) deficiency. After inconspicuous cardiopulmonary adjustment, both entered a state of metabolic crisis with respiratory insufficiency and ventilatory requirement at the 2nd and 4th day of life, respectively. Diagnosis of hyperammonemia (NH(3) > 1000 micromol/l) was followed by the detection of a plasma amino acid pattern that is typical for OTC-deficiency and an excessive orotic aciduria. Beside intravenous treatment (insulin-glucose-infusion, lipid infusion, sodium benzoate, arginine, L-carnitine), the preterm infant received an exchange transfusion and was supplied with central venous catheters, hemofiltration and hemodialysis. He died after severe disturbances of circulation and coagulation at the 14th day. The male term infant tolerated the effective hemofiltration and was dicharged home with specific therapy at day 26. CONCLUSIONS: Time of diagnosis and influence of additional risk factors are decisively for the prognosis of OTC-deficiency. The immediate aims of therapy (stabilization of vital functions, reduction of plasma ammonium, control of nutrition) can only be realized in cooperation between neonatology, division of metabolism, pediatric nephrology and pediatric surgery.

Cellular expression of TNF-alpha in human cytomegalovirus (HCMV) infection.

Human cytomegalovirus (HCMV) belongs to the most frequent human pathogens. Even if the respective pathomorphological patterns are known in detail, the mechanisms which lead to persistence of the virus in its latent form, its reactivation as well as mechanisms of cell death in the symptomatic infection remain to be clarified. It is postulated that HCMV controls expression of TNF-alpha gene and the associated secondary inflammatory response. On the other hand, TNF-alpha has been shown in in vitro studies to represent a potential stimulator of HCMV major IE promoter. The present studies have been aimed at evaluation of TNF-alpha expression in HCMV-infected brain, liver, kidney and pancreas, obtained upon autopsy from children deceased due to an inborn HCMV infection. In situ hybridisation using digoxigenin-labelled oligonucleotide probe demonstrated the expression of TNF-alpha transcript in the liver (in macrophages and endothelial cells) and in pancreatic islets of Langerhans (in beta cells). Immunocytochemical studies aimed at detection of TNF-alpha protein in the material yielded negative results.

Immunocytochemical localization of PTHrP in human and rat salivary glands.

Parathyroid hormone-related protein (PTHrP) was isolated from tumours and is thought to represent the main factor responsible for humoral hypercalcaemia, which accompanies neoplastic diseases. At present, the protein is known to reside in multiple tissues and organs of both humans and animals. Our study was aimed at demonstrating the presence of PTHrP in normal salivary glands (parotid and submandibular) of rats and humans. Application of immunocytochemical techniques permitted to document the presence of PTHrP in the human and in the rat salivary glands. In all cases, an intense reaction was observed in intra- and interlobular ducts. In rat salivary glands, PTHrP was also present in cells of mucous acini. In our opinion, the presence of PTHrP in the ducts indicates participation of the protein in electrolyte transport across the epithelial cells. The positive reaction noted in mucous acini of rat salivary glands may indicate accessory role of PTHrP in the secretory processes in the glands.

Brachytelephalangic dwarfism due to the loss of ARSE and SHOX genes resulting from an X;Y translocation.

Here we report an 8-year-old male patient who had mesomelic shortening of forearms and legs, brachytelephalangia and ichthyotic skin lesions. Chromosomal analysis showed an X;Y translocation involving the short arm of the X chromosome (Xp). Fluorescence in situ hybridization (FISH) and molecular studies localized the breakpoints on Xp22.3 in the immediate vicinity of the KAL gene demonstrating deletions of steroid sulfatase (STS), arylsulfatase E (ARSE), and short stature homeo box (SHOX) genes. It was suspected that the patient was suffering from chondrodysplasia punctata because of a loss of the arylsulfatase E (ARSE) gene. However, no stippled epiphyses were to be seen in the neonatal radiograph. Interestingly, this patient is the first case with a proven loss of the ARSE gene without chondrodysplasia punctata, assuming that chondrodysplasia punctata is not an obligatory sign of ARSE gene loss. Brachytelephalangia was the only result of ARSE gene deletion in this case. The patient's mother also had dwarfism and showed Madelung deformity of the forearms. She was detected as a carrier of the same aberrant X chromosome. The male patient did not show Madelung deformity, demonstrating that Lerri-Weill syndrome phenotype may be still incomplete in children with SHOX gene deletion. The wide clinical spectrum in the male and the Leri-Weill phenotype in his mother are the results of both a deletion involving several sulfatase genes in Xp22.3 and the SHOX gene located in the pseudoautosomal region. Nevertheless, there is no explanation for the absence of chondrodysplasia punctata despite the total loss of the ARSE gene. Further studies are necessary to investigate genotype/phenotype correlation in cases with translocations or microdeletions on Xp22.3, including the ARSE and the SHOX gene loci.

Immunolocalization of PTHrP in the submandibular glands of three rodent species.

The present study deals with immunohistochemical localization of PTHrP in bank vole, pine vole and white mouse submandibular glands. PTHrP immunoreactivity was observed in epithelial cells of all ductal segments (intercalated, striated, interlobular and main excretory ducts) of the salivary glands in all the three animal species tested. We also found PTHrP expression in myoepithelial cells surrounding the mucous alveoli of submandibular glands in those animals. The reaction was less intense than that found in the epithelial cells of excretory ducts. We occasionally observed a very slight positive reaction for PTHrP in smooth muscle cells of small blood vessels. We also found PTHrP expression in the neurons of ganglion in the submandibular gland.