Use of Spermatic Cord Block Systematically Identifies a Paraspinal Tumor as Source of Orchialgia.

Orchialgia is a common urologic complaint with a myriad of etiologies. Workup for orchialgia requires a broad differential diagnosis and a thorough understanding of relevant anatomy. We report the case of a 43-year-old man who presented to a urologist with right testicular pain. Following a negative workup, the patient received a spermatic cord block for therapeutic and diagnostic purposes. Two months after the block, the patient returned with new complaints of ipsilateral inner thigh paresthesias, suggesting a pathologic process proximal to the genital branch of the genitofemoral nerve. A subsequent MRI of the lumbosacral spine revealed a paraspinal mass involving nerve roots at L1-2. We highlight the utility of the spermatic cord block and its role in the diagnosis of a paraspinal tumor as an uncommon cause of orchialgia.

Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer's disease.

Amyloid-ß proteins (Aß) of 42 (Aß42) and 40 aa (Aß40) accumulate as senile plaques (SP) and cerebrovascular amyloid protein deposits that are defining diagnostic features of Alzheimer's disease (AD). A number of rare mutations linked to familial AD (FAD) on the Aß precursor protein (APP), Presenilin-1 (PS1), Presenilin- 2 (PS2), Adamalysin10, and other genetic risk factors for sporadic AD such as the ε4 allele of Apolipoprotein E (ApoE-ε4) foster the accumulation of Aß and also induce the entire spectrum of pathology associated with the disease. Aß accumulation is therefore a key pathological event and a prime target for the prevention and treatment of AD. APP is sequentially processed by ß-site APP cleaving enzyme (BACE1) and γ-secretase, a multisubunit PS1/PS2-containing integral membrane protease, to generate Aß. Although Aß accumulates in all forms of AD, the only pathways known to be affected in FAD increase Aß production by APP gene duplication or via base substitutions on APP and γ-secretase subunits PS1 and PS2 that either specifically increase the yield of the longer Aß42 or both Aß40 and Aß42. However, the vast majority of AD patients accumulate Aß without these known mutations. This led to proposals that impairment of Aß degradation or clearance may play a key role in AD pathogenesis. Several candidate enzymes, including Insulin-degrading enzyme (IDE), Neprilysin (NEP), Endothelin-converting enzyme (ECE), Angiotensin converting enzyme (ACE), Plasmin, and Matrix metalloproteinases (MMPs) have been identified and some have even been successfully evaluated in animal models. Several studies also have demonstrated the capacity of γ-secretase inhibitors to paradoxically increase the yield of Aß and we have recently established that the mechanism is by skirting Aß degradation. This review outlines major cellular pathways of Aß degradation to provide a basis for future efforts to fully characterize the panel of pathways responsible for Aß turnover.

Evidence of a novel mechanism for partial γ-secretase inhibition induced paradoxical increase in secreted amyloid ß protein.

BACE1 (ß-secretase) and α-secretase cleave the Alzheimer's amyloid ß protein (Aß) precursor (APP) to C-terminal fragments of 99 aa (CTFß) and 83 aa (CTFα), respectively, which are further cleaved by γ-secretase to eventually secrete Aß and Aα (a.k.a. P3) that terminate predominantly at residues 40 and 42. A number of γ-secretase inhibitors (GSIs), such as N-[N-(3,5-Difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester (DAPT), have been developed with the goal of reducing Aß to treat Alzheimer's disease (AD). Although most studies show that DAPT inhibits Aß in a dose-dependent manner several studies have also detected a biphasic effect with an unexpected increase at low doses of DAPT in cell cultures, animal models and clinical trials. In this article, we confirm the increase in Aß40 and Aß42 in SH-SY5Y human neuroblastoma cells treated with low doses of DAPT and identify one of the mechanisms for this paradox. We studied the pathway by first demonstrating that stimulation of Aß, a product of γ-secretase, was accompanied by a parallel increase of its substrate CTFß, thereby demonstrating that the inhibitor was not anomalously stimulating enzyme activity at low levels. Secondly, we have demonstrated that inhibition of an Aß degrading activity, endothelin converting enzyme (ECE), yielded more Aß, but abolished the DAPT-induced stimulation. Finally, we have demonstrated that Aα, which is generated in the secretory pathway before endocytosis, is not subject to the DAPT-mediated stimulation. We therefore conclude that impairment of γ-secretase can paradoxically increase Aß by transiently skirting Aß degradation in the endosome. This study adds to the growing body of literature suggesting that preserving γ-secretase activity, rather than inhibiting it, is important for prevention of neurodegeneration.