Histomorphology of the Penis Bone (Baculum) in the Gray Long‐Eared Bat Plecotus austriacus (Chiroptera,Vespertilionidae)

For the first time, the histomorphology of the penis bone of a bat (Plecotus austriacus) was examined in detail. From Plecotus austriacus, 14 whole penes and 11 isolated bacula were studied and compared to bacula of Plecotus auritus and Plecotus macrobullaris. The baculum was located on specimen microradiographs and in micro‐CT images in the tip of the penis. Using serial semithin sections and surface‐stained, undecalcified ground sections, the types of bone and other tissues constituting the baculum were examined by light microscopy. 3D reconstructions were generated from the serial semithin sections and from micro‐CT images. The shaft and the proximal branches of the Y‐shaped baculum form a tubular bone around a medullary cavity. Since the small diameter of this channel and the main lamellar bone around it resemble a Haversian canal, the baculum is equivalent to a single‐osteon bone. Several oblique nutrient canals enter this medullary cavity in the shaft and branches. All ends of the baculum consist predominantly of woven bone. The collagen fiber bundles of the tunica albuginea of both corpora cavernosa insert via fibrocartilage into the woven bone of the branches. Thus, the microscopic structures support the hypothesis that the baculum functions as a stiffening element in the erect penis. In this study, several microscopic imaging techniques were evaluated for displaying the microscopic structures of the baculum. Specimen microradiography, but especially micro‐CT proved to be suitable nondestructive methods for accurate and reproducible demonstration and comparison of the three‐dimensional structures of the baculum in different bat species. Anat Rec 293:1248–1258, 2010. © 2010 Wiley‐Liss, Inc.     

BACE1 and mutated presenilin-1 differently modulate Abeta40 and Abeta42 levels and cerebral amyloidosis in APPDutch transgenic mice

APPDutch transgenic (tg) mice develop cerebral amyloid angiopathy (CAA) that consists mainly of AbetaDutch40, with virtually no parenchymal amyloid plaques. To modulate cerebral amyloidosis, we crossbred APPDutch mice with either BACE1 tg mice to increase total AbetaDutch, or with G384A-mutated PS1 tg mice to elevate the ratio of AbetaDutch42 to AbetaDutch40. We analyzed all mice at 22 months of age. Compared to APPDutch mice, double-tg APPDutch/BACE1 mice revealed increased CAA mainly due to extensive vascular amyloid accumulation in the thalamus. In addition, they developed parenchymal amyloid in cortex and subiculum. In contrast, APPDutch/G384A-PS1 mice showed extensive, predominantly parenchymal amyloid throughout the entire brain, interestingly, even in the thalamus. The amyloid, composed largely of AbetaDutch42, was different compared to that in APPDutch/BACE1 mice which was composed mainly of AbetaDutch40. In summary, these mouse models reveal a broad variety and region-specificity of parenchymal versus vascular cerebral amyloid. This is partially explained by the absolute amount of neuronally produced AbetaDutch42 and AbetaDutch40 and ratio between the two. We conclude that the absolute levels of Abeta in combination with the ratio of Abeta42 to Abeta40 play a key role in determining the cerebral compartment and brain region in which Abeta is deposited.     

Mechanism of cerebral beta-amyloid angiopathy: murine and cellular models

Cerebral amyloid angiopathy of the beta-amyloid type (Abeta-CAA) is a risk factor for hemorrhagic stroke and independently is believed to contribute to dementia. Naturally occurring animal models of Abeta-CAA are scarce and not well suited for the laboratory. To this end, a variety of transgenic mouse models have been developed that, similar to cerebral Abeta-amyloidosis in humans, develop either Abeta-CAA only or both Abeta-CAA and parenchymal amyloid, or primarily parenchymal amyloid with only scarce Abeta-CAA. The lessons learned from these mouse models are: i) Abeta-CAA alone is sufficient to induce cerebral hemorrhage and associate pathologies including neuroinflammation, ii) the origin of vascular amyloid is mainly neuronal, iii) Abeta-CAA results largely from impaired Abeta clearance, iv) a high ratio Abeta40:42 favors vascular over parenchymal amyloidosis, and v) genetic risk factors such as ApoE modulate Abeta-CAA and CAA-induced hemorrhages. Therapeutic strategies to inhibit Abeta-CAA are poor at the present time. Once Abeta-CAA is present current Abeta immunotherapy strategies have failed to clear vascular amyloid and even run the risk of serious side effects. Despite this progress in deciphering the pathomechanism of Abeta-CAA, with these first generation mouse models of Abeta-CAA, refining these models is needed and will help to understand the emerging importance of Abeta-CAA for dementia and to develop biomarkers and therapeutic strategies.     

Unemployment and ill health: a connection through inflammation?

Background  

Unemployment is a source of acute and long-term psychosocial stress. Acute and chronic psychosocial stress can induce pronounced changes in human immune responses. In this study we tested our hypothesis that stress-induced low-grade tissue inflammation is more prevalent among the unemployed.     

Polymorphisms in genes controlling inflammation and tissue repair in rheumatoid arthritis: a case control study

Background  

Various cytokines and inflammatory mediators are known to be involved in the pathogenesis of rheumatoid arthritis (RA). We hypothesized that polymorphisms in selected inflammatory response and tissue repair genes contribute to the susceptibility to and severity of RA.     

Glucocorticoids, metabolism and metabolic diseases

Since the discovery of the beneficial effects of adrenocortical extracts for treating adrenal insufficiency more than 80 years ago, glucocorticoids (GC) and their cognate, intracellular receptor, the glucocorticoid receptor (GR) have been characterized as critical components of the delicate hormonal control system that determines energy homeostasis in mammals. Whereas physiological levels of GCs are required for proper metabolic control, excessive GC action has been tied to a variety of pandemic metabolic diseases, such as type II diabetes and obesity. Highlighted by its importance for human health, the investigation of molecular mechanisms of GC/GR action has become a major focus in biomedical research. In particular, the understanding of tissue-specific functions of the GC-GR pathway has been proven to be of substantial value for the identification of novel therapeutic options in the treatment of severe metabolic disorders. Therefore, this review focuses on the role of the GC-GR axis for metabolic homeostasis and dysregulation, emphasizing tissue-specific functions of GCs in the control of energy metabolism.     

The kinetics of inhibition of human acetylcholinesterase and butyrylcholinesterase by two series of novel carbamates

Controlled inhibition of brain acetyl- and butyrylcholinesterases (AChE and BChE, respectively) and of monoamine oxidase-B (MAO-B) may slow neurodegeneration in Alzheimer's and Parkinson's diseases. It was postulated that certain carbamate esters would inhibit AChE and BChE with the concomitant release in the brain of the OH-derivatives of rasagiline or selegiline that can serve as inhibitors of MAO-B and as antioxidants. We conducted a detailed in vitro kinetic study on two series of novel N-methyl, N-alkyl carbamates and compared them with rivastigmine, a known anti-Alzheimer drug. The rates of carbamylation (k(i)) and decarbamylation (k(r)) of recombinant human AChE were mainly determined by the size of the N-alkyl substituent and to a lesser extent by the nature of the leaving group. k(i) was highest when the alkyl was methyl, hexyl, cyclohexyl, or an aromatic substituent and lowest when it was ethyl. This suggested that k(i) depends on a delicate balance between the length of the residue and its degree of freedom of rotation. By contrast, presumably because of its wider gorge, inhibition of human BChE was less influenced by the size of the alkyl group and more dependent on the structure of the leaving group. The data show how the degree of enzyme inhibition can be manipulated by structural changes in the N-methyl, N-alkyl carbamates and the corresponding leaving group to achieve therapeutic levels of brain AChE, BChE, and MAO-B inhibition.