Comparison of a pocket-size ultrasound device with a premium ultrasound machine: diagnostic value and time required in bedside ultrasound examination.

PURPOSE: Time savings and clinical accuracy of a new miniature ultrasound device was investigated utilizing comparison with conventional high-end ultrasound instruments. Our objective was to determine appropriate usage and limitations of this diagnostic tool in internal medicine. METHODS: We investigated 28 patients from the internal-medicine department. Patients were examined with the Acuson P10 portable device and a Sonoline Antares instrument in a cross-over design. All investigations were carried out at the bedside; the results were entered on a standardized report form. The time for the ultrasound examination (transfer time, setting up and disassembly, switching on and off, and complete investigation time) was recorded separately. RESULTS: Mean time for overall examination per patient with the portable ultrasound device was shorter (25.0 ± 4.5 min) than with the high-end machine (29.4 ± 4.4 min; p < 0.001). When measuring the size of liver, spleen, and kidneys, the values obtained differed significantly between portable device and the high-end instrument. In our study, we identified 113 pathological ultrasound findings with the high-end ultrasound machine, while 82 pathological findings (73%) were concordantly detected with the portable ultrasound device. The main diagnostic strengths of the portable device were in the detection of ascites (sensitivity 80%), diagnosis of fatty liver, and identification of severe parenchymal liver damage. CONCLUSIONS: The clinical utility of portable ultrasound machines is limited. There will be clinical roles for distinct clinical questions such as detection of ascites or pleural effusion when used by experienced examiners. However, sensitivity in detecting multiple pathologies is not comparable to high-end ultrasound machines.

Activation of the mouse odorant receptor 37 subsystem coincides with a reduction of novel environment-induced activity within the paraventricular nucleus of the hypothalamus.

Within the main olfactory system of mammals, a unique subsystem exists that is comprised of sensory neurons expressing odorant receptors (ORs) of the OR37 subfamily. These receptors are exclusive for mammals and are highly conserved across species. The mouse OR37 receptor subtypes A, B and C were shown to be activated by the long-chain aliphatic aldehydes pentadecanal, hexadecanal and heptadecanal, respectively. The search for biological sources of these compounds showed that bodily secretions from conspecifics activated the OR37A, B and C glomerulus. At the same time, the activity of cells in a target region of projection neurons from OR37 glomeruli, the paraventricular nucleus of the hypothalamus (PVN), was reduced compared with controls (clean test box). A large number of the activated cells in the PVN of mice that were placed into a clean test box were corticotropin-releasing hormone cells, indicating an induction of the stress axis due to the novel environment. The much lower number of activated cells of mice in a box enriched with bodily secretions from conspecifics indicated a reduced stress response. As bodily secretions from conspecifics activated the OR37 system and simultaneously reduced stress-induced activation of the PVN, it was tested whether the ligands for OR37 receptors could induce this effect. Indeed, a similarly reduced activity in the PVN was found in mice kept in a clean test box and exposed to a mixture of the OR37 ligands delivered via an air stream. These data indicate that the OR37 system may play a role in mediating a phenomenon called social buffering.

Connectivity from OR37 expressing olfactory sensory neurons to distinct cell types in the hypothalamus.

Olfactory sensory neurons (OSNs) which express a member from the OR37 subfamily of odorant receptor (OR) genes are wired to the main olfactory bulb (MOB) in a unique monoglomerular fashion; from these glomeruli an untypical connectivity into higher brain centers exists. In the present study we have investigated by DiI and transsynaptic tracing approaches how the connection pattern from these glomeruli into distinct hypothalamic nuclei is organized. The application of DiI onto the ventral domain of the bulb which harbors the OR37 glomeruli resulted in the labeling of fibers within the paraventricular nucleus (PVN) and supraoptic nucleus (SO) of the hypothalamus; some of these fibers were covered with varicose-like structures. No DiI-labeled cell somata were detectable in these nuclei. The data indicate that projection neurons which originate in the OR37 region of the MOB form direct connections into these nuclei. The cells that were labeled by the transsynaptic tracer WGA in these nuclei were further characterized. Their distribution pattern in the paraventricular nucleus was reminiscent of cells which produce distinct neuropeptides. Double labeling experiments confirmed that they contained vasopressin, but not the related neuropeptide oxytocin. Morphological analysis revealed that they comprise of magno- and parvocellular cells. A comparative investigation of the WGA-positive cells in the SO demonstrated that these were vasopressin-positive, as well, whereas oxytocin-producing cells of this nucleus also contained no transsynaptic tracer. Together, the data demonstrates a connectivity from OR37 expressing sensory neurons to distinct hypothalamic neurons with the same neuropeptide content.

IkappaBbeta is an essential co-activator for LPS-induced IL-1beta transcription in vivo.

Inhibitor of κB (IκB) ß (IκBß) represents one of the major primary regulators of NF-κB in mammals. In contrast to the defined regulatory interplay between NF-κB and IκBα, much less is known about the biological function of IκBß. To elucidate the physiological role of IκBß in NF-κB signaling in vivo, we generated IκBß-deficient mice. These animals proved to be highly refractory to LPS-induced lethality, accompanied by a strong reduction in sepsis-associated cytokine production. In response to LPS, IκBß is recruited to the IL-1ß promoter forming a complex with the NF-κB subunits RelA/c-Rel required for IL-1ß transcription. Further transcriptome analysis of LPS-stimulated wild-type and IκBß-deficient BM-derived macrophages revealed several other genes with known regulatory functions in innate immunity arguing that a subset of NF-κB target genes is under control of IκBß. Collectively, these findings provide an essential proinflammatory role for IκBß in vivo, and establish a critical function for IκBß as a transcriptional coactivator under inflammatory conditions.

The alternative NF-kappaB signalling pathway is a prerequisite for an appropriate immune response against lymphocytic choriomeningitis virus infection.

Two major nuclear factor-kappaB (NF-kappaB) signalling pathways are involved in the regulation of the immune response. While the classical NF-kappaB pathway is responsible for regulation of genes encoding components of the innate immune response, the alternative NF-kappaB signalling pathway mediates processes of the adaptive immune system. To evaluate the role of the NF-kappaB signalling pathways in the control of viral infection, we have used lymphocytic choriomeningitis virus (LCMV) infection of mice, which is known to be an excellent model for studying antiviral immune responses. Via the use of mice that were deficient in NF-kappaB subunits from either the classical (p50(-/-) mice) or the alternative NF-kappaB pathway (p52(-/-) mice), we were able to demonstrate that the alternative NF-kappaB pathway is required for the T-cell-mediated immune response against LCMV. Mice that were deficient in the alternative NF-kappaB pathway subunit p52 showed an impaired T-cell response against LCMV infection. Furthermore, these mice also showed an impaired T-cell-dependent humoral immune response against vesicular stomatitis virus (VSV) infection. Adoptive transfer experiments revealed that impaired priming, but not the T-cell response itself, was responsible for the defective cellular immune response against LCMV infection. Our data demonstrate that a functional alternative NF-kappaB signalling pathway is required to assure an adequate immune response after viral infection.

Conditional ablation of Notch signaling in pancreatic development.

The role of the Notch signaling members Notch1, Notch2 and Rbpj in exocrine pancreatic development is not well defined. We therefore analyzed conditional pancreas-specific Rbpj and combined Notch1/Notch2 knockout mice using Ptf1a(+/Cre(ex1)) mice crossed with floxed Rbpj or Notch1/Notch2 mice. Mice were analyzed at different embryonic stages for pancreatic exocrine and endocrine development. The absence of Rbpj in pancreatic progenitor cells impaired exocrine pancreas development up to embryonic day 18.5 and led to premature differentiation of pancreatic progenitors into endocrine cells. In Rbpj-deficient pancreata, amylase-expressing acini and islets formed during late embryonic and postnatal development, suggesting an essential role of Rbpj in early but not late development. Contrary to this severe phenotype, the concomitant inactivation of Notch1 and Notch2 only moderately disturbed the proliferation of pancreatic epithelial cells during early embryonic development, and did not inhibit pancreatic development. Our results show that, in contrast to Rbpj, Notch1 and Notch2 are not essential for pancreatogenesis. These data favor a Notch-independent role of Rbpj in the development of the exocrine pancreas. Furthermore, our findings suggest that in late stages of pancreatic development exocrine cell differentiation and maintenance are independent of Rbpj.

VHL mutations in renal cell cancer: does occupational exposure to trichloroethylene make a difference?

Occupational exposures have long been suspected to play a role in the incidence of renal cell carcinoma (RCC). Especially, the carcinogenicity of the industrial solvent trichloroethylene (TCE) has been controversially debated, both with respect to the epidemiological and the molecular studies. In order to further elucidate this issue, it appeared important to compare suitable RCC patient groups, i.e., TCE-exposed versus non-TCE-exposed patients. We evaluated RCC from a previous German study that had described differences in RCC risks between TCE-exposed (n=17) and non-exposed patients (n=21). We compared age at diagnosis and histopathologic parameters of tumors as well as somatic mutation characteristics in the kidney cancer causing VHL tumor suppressor gene. RCC did not differ with respect to histopathological characteristics in both patient groups. We noticed a younger age at diagnosis in TCE-exposed patients compared to non-exposed patients (P=0.01). Moreover, the non-TCE-exposed patients did not share the somatic VHL mutation characteristics of TCE-exposed patients such as the previously identified hot spot mutation 454 C > T P81S or multiple mutations. These data support the notion of a putative genotoxic effect of TCE leading to VHL gene damage and subsequent occurrence of RCC in highly exposed subjects.

VHL2C phenotype in a German von Hippel-Lindau family with concurrent VHL germline mutations P81S and L188V.

Von Hippel-Lindau disease (VHL) is a multitumor syndrome that develops on the basis of germline mutations in the VHL tumor suppressor gene. Genotype-phenotype correlations have helped to stratify the disease into VHL type 1 (without pheochromocytoma) and VHL type 2A, 2B, and 2C (with pheochromocytoma). VHL2C is characterized by a pheochromocytoma-only phenotype. We report on the P81S germline mutation in a German VHL2C family with the previously identified L188V mutation. The concurrent P81S mutation was identified by novel screening approaches including denaturing HPLC and sequencing. We show the co-segregation of these two mutations with the disease and discuss their possible impact on pVHL function and phenotype.