Owner expectations regarding antimicrobial prescription for canine acute diarrhea: A prospective observational study from the capital of Denmark.

Acute diarrhea is a common condition in dogs. Most cases are mild and self-limiting and according to guidelines, antimicrobial treatment is only indicated in dogs with severe systemic disease. However, antimicrobials are still prescribed in 50-65 % of mild cases. Multiple factors have been shown to influence the antimicrobial prescription decision, including perceived pressure from pet owners. This study aimed to investigate dog owners' expectations regarding antimicrobial prescription for dogs with acute diarrhea and the attending veterinarians' perceived owner expectation. To investigate this, a structured telephone interview with owners and a post-consultation questionnaire for the attending veterinarians were conducted. Ninety-nine unique dog-consultations were included with a 91 % owner response rate (n = 90), in these cases 63 % of veterinarians responded (n = 57). Only 6/90 (7 %) owners expressed an expectation of antimicrobial prescription. Of these, two expressed dissatisfaction that antimicrobials were withheld. In 5/57 cases, the attending veterinarian perceived an expectation to prescribe antimicrobials. Three cases aligned with an actual owner expectation, the latter two were pure perception. Eighty percent of owners expressed satisfaction with the consultation in general (n = 72/90), while 16 % (14/90) and 4 % (4/90) expressed minor or major dissatisfaction with non-treatment related issues, respectively. In this study, very few dog owners expressed an expectation of antimicrobials for treatment of acute diarrhea. Likewise, the veterinarians perceived an expectation in only a minority of cases, however, the actual and perceived expectation did not always align. In conclusion, this study suggests that an overall high owner satisfaction is feasible despite a non-antimicrobial approach.

Gonadoblastoma Y locus genes expressed in germ cells of individuals with dysgenetic gonads and a Y chromosome in their karyotypes include DDX3Y and TSPY.

STUDY QUESTION: Which Y genes mapped to the 'Gonadoblastoma Y (GBY)' locus on human Y chromosome are expressed in germ cells of individuals with some Differences of Sexual Development (DSD) and a Y chromosome in their karyotype (DSD-XY groups)? SUMMARY ANSWER: The GBY candidate genes DDX3Y and TSPY are expressed in the germ cells of DSD-XY patients from distinct etiologies: patients with mixed gonadal dysgenesis (MGD) and sex chromosome mosaics (45,X0/46,XY; 46,XX/46,XY); patients with complete androgen insensitivity (CAIS), patients with complete gonadal dysgenesis (CGD; e.g. Swyer syndrome). WHAT IS KNOWN ALREADY: A GBY locus was proposed to be present on the human Y chromosome because only DSD patients with a Y chromosome in their karyotype have a high-although variable-risk (up to 55%) for germ cell tumour development. GBY was mapped to the proximal part of the short and long Y arm. TSPY located in the proximal part of the short Y arm (Yp11.1) was found to be a strong GBY candidate gene. It is expressed in the germ cells of DSD-XY patients with distinct etiologies but also in foetal and pre-meiotic male spermatogonia. However, the GBY region extends to proximal Yq11 and therefore includes probably more than one candidate gene. STUDY DESIGN, SIZE, DURATION: Protein expression of the putative GBY candidate gene in proximal Yq11, DDX3Y, is compared with that of TSPY in serial gonadal tissue sections of 40 DSD-XY individuals from the three DSD patient groups (MGD, Complete Androgen Insensitivity Syndrome [CAIS], CGD) with and without displaying malignancy. Expression of OCT3/4 in the same tissue samples marks the rate of pluripotent germ cells. PARTICIPANTS/MATERIALS, SETTING, METHOD: A total of 145 DSD individuals were analysed for the Y chromosome to select the DSD-XY subgroup. PCR multiplex assays with Y gene specific marker set score for putative microdeletions in GBY Locus. Immunohistochemical experiments with specific antisera mark expression of the GBY candidate proteins, DDX3Y, TSPY, in serial sections of the gonadal tissue samples; OCT3/4 expression analyses in parallel reveal the pluripotent germ cell fraction. MAIN RESULTS AND THE ROLE OF CHANCE: Similar DDX3Y and TSPY protein expression patterns were found in the germ cells of DSD-XY patients from each subgroup, independent of age. In CAIS patients OCT3/4 expression was often found only in a fraction of these germ cells. This suggest that GBY candidate proteins are also expressed in the non-malignant germ cells of DSD-XY individuals like in male spermatogonia. LIMITATIONS, REASONS FOR CAUTION: Variation of the expression profiles of GBY candidate genes in the germ cells of some DSD-XY individuals suggests distinct transcriptional and translational control mechanisms which are functioning during expression of these Y genes in the DSD-XY germ cells. Their proposed GBY tumour susceptibility function to transform these germ cells to pre-malignant GB/Germ Cell Neoplasia in Situ (GB/GCNIS) cells seems therefore to be limited and depending on their state of pluripotency. WIDER IMPLICATIONS OF THE FINDINGS: These experimental findings are of general importance for each individual identified in the clinic with DSD and a Y chromosome in the karyotype. To judge their risk of germ cell tumour development, OCT3/4 expression analyses on their gonadal tissue section is mandatory to reveal the fraction of germ cells still being pluripotent. Comparative expression analysis of the GBY candidate genes can be helpful to reveal the fraction of germ cells with genetically still activated Y chromosomes contributing to further development of malignancy if at high expression level. STUDY FUNDING/COMPETING INTEREST(S): This research project was supported by a grant (01GM0627) from the BMBF (Bundesministerium für Bildung und Forschung), Germany to P.H.V. and B.B. The authors have no competing interests.

Characteristics, management modalities and outcome in chronic systolic heart failure patients treated in tertiary care centers: results from the EVIdence based TreAtment in Heart Failure (EVITA-HF) registry.

BACKGROUND: Limited data exist regarding baseline characteristics and management of heart failure with reduced ejection fraction (EF) in tertiary care facilities. METHODS: EVITA-HF comprises web-based case report data on demography, comorbidities, diagnostic and therapy measures, quality of life, adverse events and 1-year follow-up of patients hospitalized for chronic heart failure and an ejection fraction of less than 40%. RESULTS: Between February 2009 and June 2011, a total of 1,853 consecutive, hospitalized patients (pts) were included in 16 centers in Germany. Mean age was 70 years, 76% were male. Median EF was 30%, and 63% were in NYHA III/IV. Ischemic cardiomyopathy was present in 56%, history of hypertension in 76%, diabetes in 39%, impaired renal function in 33%, thyroid dysfunction in 12%, and malignoma in 7%. Sixty-eight percent of pts had a non-elective admission. Rhythm was sinus/atrial fibrillation or flutter/pacemaker in 64, 28 and 11%, respectively. Median heart rate amounted to 80 bpm, median blood pressure to 122/74 mmHg. LBBB was present in 26% of non-pacemaker pts. Eighteen percent had an ICD or CRT-D. Medication (admission vs. discharge) consisted of ACEI or ARB in 73 vs. 88%, ß-blocker in 71 vs. 89%, mineral corticosteroid receptor antagonist (MRA) in 32 vs. 57%, diuretics in 68 vs. 83% (p < 0.001 for each). Forty-two percent of pts received a specific treatment procedure beyond pharmacotherapy, of these 48% revascularization, 39% device therapy, 14% electrical cardioversion, 5% ablation procedures, 9 % valvular procedures, 6% iv inotropes, 1.8% IABP or LVAD implantation. At discharge, 33% of survivors had ICD- or CRT-D implants. One-year mortality amounted to 16.8%, and death or rehospitalization to 56%. NYHA class III/IV was found in 30% (p < 0.001 vs. index admission), general health status was improved in 45% and unchanged in 36% of patients. Eighty-five percent of pts took ACEI or ARB, 86% ß-blockers, 47% MRA, and 78% diuretics (p < 0.001 vs. index discharge for all). CONCLUSION: Patients with chronic heart failure and low ejection fraction represent an elderly and multimorbid population. While hospitalized, they experience a significant optimization of prognosis-relevant medication, revascularization and device therapy. After 1 year, mortality is moderate; drug adherence is high and NYHA status favourable. The EVITA-HF registry is able to reflect coherently the real-world management, efforts and follow-up in heart failure pts managed in tertiary care facilities.

Pseudoautosomal inheritance of Léri-Weill syndrome: what does it mean?

The short stature homeobox (SHOX) gene is located in the pseudoautosomal region 1 of both sex chromosomes. Haploinsufficiency of SHOX leads to different phenotypes ranging from isolated short stature to Léri-Weill syndrome characterized by short stature, mesomelia and Madelung deformity. We describe a family with a SHOX deletion originally located on the Y chromosome and transmitted from father to daughter by crossover during meiosis. The male index patient presented with short stature, mesomelia and mild Madelung deformity. His father had a normal height but slightly disproportionate short legs. The sister of the index patient presented with marked Madelung deformity and normal height. A deletion of the SHOX gene was identified in the male index patient, his father and his sister. Metaphase fluorescence in situ hybridization (FISH) analyses showed a deletion of the SHOX gene on the Y chromosomes of the index patient and his father, and on the X chromosome of his sister, indicating that a meiotic crossover of the SHOX gene region between the X and Y chromosomes had occurred. The pseudoautosomal region 1 is a known recombination 'hot spot' in male meiosis. Published genetic maps indicate high recombination frequency of ∼40% for SHOX in male meiosis leading to pseudoautosomal inheritance.

Efficacy of sublingual swallow immunotherapy in children with severe grass pollen allergic symptoms: a double-blind placebo-controlled study.

BACKGROUND: Local application of allergen extracts in specific immunotherapy is accompanied by increased compliance and significantly reduced side effects. However, efficacy of local immunotherapy in children has yet not been sufficiently demonstrated. This study was performed to determine clinical efficacy of high dose sublingual swallow immunotherapy (SLIT) by a double-blind placebo-controlled study in children with grass pollen allergy using high dose allergen extracts. METHODS: A total of 161 children with seasonal rhinoconjunctivitis of which, 68 had also asthma symptoms were enrolled in a multicenter double-blind placebo-controlled study for 1 year and treated on a daily basis with sublingually applied allergen drops. After 1 year all children were given treatment for another 2 years in an open-controlled setting. Symptom scores and medication were assessed during the pollen seasons with structured interviews. Applied allergen dosage, compliance, and side effects were documented by daily diary cards. Primary endpoint was a clinical index (CI) combining symptom scores with medication index. Titrated skin prick tests (SPT) and specific antibody measurements were performed each year. RESULTS: Combining symptom with medication scores to CI was highly reliable (reliability coefficient = 0.89, standard error = 9.6%). Allergen-specific IgE- and IgG-subclass antibodies increased significantly in patients treated with SLIT indicating an activation of the immune response induced by the locally applied grass pollen extract. SPT reactivity did not change during therapy. After 1 year of SLIT in the original design we observed no significant difference in the CI between treatment and placebo analyzing all patients included in the study per intention to treat and per protocol. However, subgroup analysis in a repeated measures model revealed that patients with SLIT and severe symptoms before the beginning of treatment (CI > mean/ > 1.51) showed a significant improvement of clinical symptoms after 3 years. CONCLUSION: In this study SLIT was accompanied by a significant placebo effect. Efficacy of treatment could only be seen in children with severe clinical symptoms and this became clinically marked after 3 years of therapy.

Congenital disorder of glycosylation IId (CDG-IId) -- a new entity: clinical presentation with Dandy-Walker malformation and myopathy.

A 1.5-year-old boy with macrocephaly due to a Dandy-Walker malformation presented with progressive hydrocephalus, extensive muscular hypotonia, transient cholestatic syndrome, extensive coagulation abnormalities and elevated creatine kinase indicating myopathy. Diagnostic work-up indicated a congenital disorder of glycosylation (CDG, formerly carbohydrate deficient glycoprotein syndrome). The serum transferrin pattern obtained by automated isoelectric focusing (IEF) showed an hitherto unreported pattern with strongly elevated tri-, di-, mono- and asialotransferrin bands, increasing in this order together with markedly decreased tetrasialotransferrin. Investigation of two additional glycoproteins, alpha(1)-antitrypsin and alpha(1)-antichymotrypsin, confirmed a generalised defect of glycosylation. All known glycosylation defects could be ruled out by enzymatic analyses in either leukocytes or fibroblasts or by the results obtained by IEF. SDS-electrophoresis demonstrated a marked difference in the molecular weight of transferrin, suggesting the lack of parts or of all oligosaccharide chains. The defect could be delineated to a deficiency of beta-1,4-galactosyltransferase (E.C.2.4.1.38) due to a homozygous insertion (1031 - 1032 insC). Details of the biochemical and molecular findings will be described elsewhere.

Complete virilization in congenital adrenal hyperplasia: clinical course, medical management and disease-related complications.

OBJECTIVE: In girls with congenital adrenal hyperplasia (CAH), genital ambiguity usually leads to a rapid neonatal diagnosis. Rarely, CAH causes complete virilization and male sex assignment with a delayed diagnosis. After being confronted with very specific problems in two of such patients, we collected data of patients with CAH and complete virilization in a nationwide study to delineate specific problems of these rare patients in order to improve their management. DESIGN AND PATIENTS: Through the German Working Group of Paediatric Endocrinology (Arbeitsgemeinschaft Pädiatrische Endokrinologie, APE), questionnaires were sent to all members caring for patients with CAH and complete virilization in their endocrine clinics. Data from 16 patients from 10 paediatric endocrine centres were assessed by questionnaire. RESULTS: The following problems have been encountered. (1) Sex assignment/gender identity: initially all patients had a male sex assignment. Six patients were diagnosed during the first month of life. Five were reassigned to female sex immediately, one at the age of 19 months. Except in one girl demonstrating some tomboyish behaviour, gender role behaviour in these patients did not differ from unaffected girls. Ten patients were diagnosed late at 3.4--7 years of age. In seven patients with a late diagnosis, male sex assignment was maintained; one of them expressed some concerns about living as a male. In three patients late sex reversal was performed, gender identity is very poor in one and new sex assignment is currently under consideration. (2) SURGERY: irrespective of the sex assigned, all patients had between one and three surgical procedures, including clitoris reduction and (repeated) vaginoplasties in patients with female sex assignment. Hysterectomy and ovarectomy were performed in patients with male sex assignment. (3) Short stature: patients with a late diagnosis of CAH had extremely advanced bone ages of +6.3 to +9.5 years, leading to severely reduced final height of 137 to 150 cm in adult patients. Patients tended to follow height percentiles of genetic females. One pubertal patient was suicidal due to short stature. (4) Central precocious puberty (CPP): prolonged exposition to adrenal androgens led to CPP in one patient. He was treated with GnRH analogues until gonadectomy. CONCLUSIONS: Patients with CAH and complete virilization have a high risk of being diagnosed late. There are major problems and uncertainties of the patients' families and the treating physicians concerning gender assignment. Gender identity is disturbed in some patients. In addition, multiple surgical procedures are necessary and short stature as well as central precocious puberty might be important to avoid late sequelae. While some surgical interventions are probably unavoidable, most of these issues could be resolved with an early diagnosis. Thus, especially for these patients, a neonatal screening programme for CAH would be of paramount importance.

Phaeochromocytoma associated with a de novo VHL mutation as form fruste of von Hippel-Lindau disease.

UNLABELLED: Phaeochromocytomas usually occur sporadically but may be associated with dominant inherited cancer syndromes such as multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau disease (VHL) and type 1 neurofibromatosis. We report on a boy presenting at age 8 years with an isolated benign phaeochromocytoma of the left adrenal. Three years later a second adrenal phaeochromocytoma was diagnosed on the right side and removed. His family history was negative. Genetic analysis did not show a mutation in the MEN 2 susceptible proto-oncogene rearranged during transfection; however, we found a germline missense mutation in the VHL gene (nucleotide 695 G to A transversion) which has been described only twice before in the literature. Both parents had normal (wild type) VHL copies indicating that our patient had a de novo germline VHL mutation. Careful clinical evaluation of the patient at 18 years did not reveal any other manifestations of VHL disease. CONCLUSION: Carriers of von Hippel-Lindau germline mutations can present with a form fruste of von Hippel-Lindau disease presenting initially with unilateral phaeochromocytoma and therefore mutation analysis should be carried out.

Disseminated choriocarcinoma in infancy is curable by chemotherapy and delayed tumour resection.

Infantile choriocarcinoma has a poor prognosis with only 2 surviving children reported in the literature. 2 additional successfully treated children are presented. 2 infants (age 3 and 4 months at diagnosis) suffering from rapidly progressive choriocarcinoma with widespread haematogenous metastases involving the liver were treated according to the cooperative germ cell tumour treatment protocol (MAKEI 96) of the German Society of Pediatric Oncology and Hematology (GPOH). PEI-chemotherapy (cisplatin, etoposide, ifosfamide; no ifosfamide before the age of 4 months) was combined with delayed tumour resection. Treatment resulted in sustained remission in both children (event-free survival 42 and 40 months). Interphase fluorescent in situ hybridisation (FISH) analysis of the paraffin-embedded tumour sample from case one revealed four to eight copies of chromosomes X, 1 and 17 and two Y chromosomes. Hybridisation with sub-telomere and centromere specific probes for chromosome 1 displayed an imbalance between the short and long arms of chromosome 1. In the tumour cells from case 2, only a polysomy of chromosome X could be proven, other aberrations were not analysed in this case for technical reasons.

A novel mutation in the thiamine responsive megaloblastic anaemia gene SLC19A2 in a patient with deficiency of respiratory chain complex I.

The thiamine transporter gene SLC19A2 was recently found to be mutated in thiamine responsive megaloblastic anaemia with diabetes and deafness (TRMA, Rogers syndrome), an early onset autosomal recessive disorder. We now report a novel G1074A transition mutation in exon 4 of the SLC19A2 gene, predicting a Trp358 to ter change, in a girl with consanguineous parents. In addition to the typical triad of Rogers syndrome, the girl presented with short stature, hepatosplenomegaly, retinal degeneration, and a brain MRI lesion. Both muscle and skin biopsies were obtained before high dose thiamine supplementation. While no mitochondrial abnormalities were seen on morphological examination of muscle, biochemical analysis showed a severe deficiency of pyruvate dehydrogenase and complex I of the respiratory chain. In the patient's fibroblasts, the supplementation with high doses of thiamine resulted in restoration of complex I activity. In conclusion, we provide evidence that thiamine deficiency affects complex I activity. The clinical features of TRMA, resembling in part those found in typical mitochondrial disorders with complex I deficiency, may be caused by a secondary defect in mitochondrial energy production.

Characterization of eleven novel mutations (M45L, R119H, 544delG, G145V, H154Y, C184Y, D289V, 862+5A, 1172delC, R411X, E459K) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in patients with severe hypophosphatasia. Mutations in brief no. 217. Online.

Hypophosphatasia is a rare inherited disorder characterized by defective bone mineralization and deficiency of serum and tissue liver/ bone/kidney tissue alkaline phosphatase (L/B/K ALP) activity. We report the characterization of tissue-nonspecific alkaline phosphatase (TNSALP) gene mutations in a series of 9 families affected by severe hypophosphatasia. Fourteen distinct mutations were found, 3 of which were previously reported in the North American or Japanese populations. Seven of the 11 new mutations were missense mutations (M45L, R119H, G145V, C184Y and H154Y, D289V, E459K), the four others were 2 single nucleotide deletions (544delG and 1172delC), a mutation affecting donor splice site (862 + 5A) and a nonsense mutation (R411X).

Functioning thoracic paraganglioma: association with Von Hippel-Lindau syndrome.

Functioning thoracic paraganglioma (pheochromocytoma) is unusual and therefore suggestive of a pathogenesis distinct from that of sporadic adrenal pheochromocytoma. To determine whether the pheochromocytoma-associated syndromes Von Hippel-Lindau disease (VHL) and multiple endocrine neoplasia type 2 (MEN 2) play a role in the development of thoracic functioning paragangliomas, germline DNA from five unselected patients with this rare tumor was analyzed for mutations in the genes that predispose to VHL and MEN 2. Genetic investigations and further clinical data revealed that three had VHL, with two different germline mutations of the vhl gene, but no individual was affected by MEN 2. Two of the three patients with VHL did not show any additional VHL-associated lesions. This result suggests that VHL should be considered in the differential diagnosis of thoracic pheochromocytoma, as such a diagnosis carries further important implications for the patient and family. Conversely, in patients suspected of a catecholamine-secreting tumor and known VHL, thoracic localization should be considered if an adrenal pheochromocytoma cannot be detected.

[Current status of vaccination and antibiotic prophylaxis in splenectomy. II: Children]. / Standortbestimmung der Impf- und Antibioticaprophylaxe bei Splenektomie. Teil II: Kinder.

Children are exposed to a greater risk than adults for severe late postsplenectomy infection. Therefore, prophylaxis against bacterial infections need to be more extensive. This paper presents a protocol for preventive measures in children. Repeated education of the patient and his/her parents about the consequences of splenic loss is mandatory. Vaccinations against Streptococcus pneumoniae and Hemophilus influenzae are highly recommended and also against Neisseria meningitidis in certain situations. The importance of long-term antibiotic prophylaxis in children is emphasized. Recent advances in vaccine development and the increasing problems with antibiotic resistance are discussed.

[In situ detection of EGF receptor mRNA in arteriosclerotic lesions in man: implications for the proliferative activity of smooth muscle cells]. / In-situ-Nachweis von EGF-Rezeptor-mRNA in Arteriosklerose Läsionen des Menschen: Implikationen für die proliferative Aktivität glatter Muskelzellen.

Growth factors and growth factor receptors are considered to be key elements in the pathogenesis of arteriosclerosis and restenosis formation. To study the local expression of epidermal growth factor (EGF) receptor, plaque tissue specimens from advanced lesions (10 coronary, two femoral, seven carotid) of 19 patients were taken for in situ hybridization studies using an EGF-specific cDNA probe. In serial vascular sections of three lesions with increased focal cellularity, autoradiographic silver grains were clearly localized to intimal cells adjacent to the internal elastic lamina. EGF mRNA transcripts were not observed in the fibrous cap, the plaque shoulders, necrotic intimal areas, or in the media. In smooth muscle cells (SMCs) cultured from human plaque tissue, EGF increased SMC proliferative activity in a dose-dependent manner (ED50: 3-6 ng of EGF/ml). Proliferative responsiveness to EGF (10 ng/ml) was found to be significantly (p < 0.01) enhanced in coronary SMCs derived from restenotic lesions as compared to those from primary stenoses. The expression of EGF receptor mRNA in human atheromatous lesions could be of prognostic value to predict an increased SMC proliferative response to stimulatory growth factors.