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The HSAN1 is the most common of the HSANs and is inherited in an autosomal-dominant fashion HSAN1 usually presents in the second through fourth decades and this later age of onset is helpful in distinguishing it from other subtypes of HSANs, which typically manifest in infancy or childhood195 197 HSAN1 is slowly progressive and predominantly affects the small myelinated and unmyelinated nerve bers, resulting in the loss of pain and temperature sensation in the feet and hands This can lead to the development of deep dermal ulcerations, recurrent osteomyelitis, Charcot joints, bone loss, gross foot and hand deformities, and amputated digits Although most people with HSAN1 do not complain of numbness, they often describe burning, aching, or lancinating pains Autonomic neuropathy is not a prominent feature, but bladder dysfunction and reduced sweating in the feet may occur On examination, there is reduced sensation to all modalities, particularly to pin prick and temperature Mild-to-moderate distal arm and leg weakness develop over time However, some individuals develop severe distal extremity weakness early in the course197 Muscle stretch re exes are usually absent at the ankles but may be normal or reduced elsewhere As with CMT, pes cavus and hammertoe deformities can be seen HSAN1A is caused by mutations in the serine palmitolytransferase long chain base-1 (SPTLC1) gene that is located on chromosome 9q22199 201 Serine palmitolytransferase catalyzes the rate-limiting, regulatory step in the biosynthesis of sphingolipids, and the autosomaldominant inheritance suggests that the mutations either cause a gain of function of the enzyme or result in dominant-negative inhibition200 Mutations in SPTLC1 in lymphoblast cell lines cause an increase in the de novo synthesis of ceramide (a sphingolipid) that appears to trigger apoptotic cell death201 There are reports of HSAN1-like neuropathy with either an autosomal-recessive or an X-linked form of inheritance, suggesting some genetic heterogeneity HSAN1B associated with cough and gastroesophageal re ux in a large Australian family has been linked to chromosome 3p22 p24202.

Figure 23 6 (Continued)

b) Change the cursor s blink rate and test it c) Change the key repeat rate and delay settings A minor adjustment here can really help a heavy ngered user d) Close the Keyboard applet

Figure 23 6 (Continued) Schematic representation of a normal presynaptic terminal with constituent proteins, synaptic vesicles and depiction of vesicle fusion with exocytotic ACh release, junctional folding, localization of AChR, acetylcholine receptor and sodium channels

ReadDeviceData WriteDeviceData PowerMgmt ProtServ SurroundingsDD SwEvent TrustedUI Table 7-6

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The lateral boundary of the synaptic space is a porous basement membrane, which permits communication between the synaptic space and the extracellular region Communication also exists between the muscle ber s transverse tubules and the secondary synaptic clefts468,469 The synaptic cleft is not empty but lled with an extension of the basement membrane covering the external surface of both the terminal nerve and the muscle ber Of particular importance in mature NMJs is AChE, the enzyme responsible for degrading ACh into acetate and choline AChE is attached to the base-

The Mouse applet can have many different looks, depending on whether the system uses a default Windows driver or special drivers for the particular mouse You may have to explore your applet to nd these settings

ment membrane through a collagen tail (ColQ) and is present only in the synaptic region470 This process of ACh catalysis is one of the fastest enzymatic processes known and occurs at a rate of ve ACh molecules per millisecond471,472 Despite this, ACh enjoys a competitive advantage as the density of AChR (15 30K m2 ) is 5 10 times greater than the molecular density of AChE (2 3 103 /m2 )473 475 This allows 50 75% of the quantal content to achieve successful interaction with AChR under normal circumstances333,476 Temperature changes have effects on a number of different aspects of NMT Reduced temperature slows the rate of AChE hydrolysis

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Read access to confidential device settings (List of installed applications, lock PIN code, etc) Write access to confidential device settings (Time zone, lock PIN code, etc) Kill arbitrary processes, power off peripherals, or enter standby Register an IPC server whose name contains a ! character Limits the risk of impersonation by less trusted processes Low-level access to location-awareness devices (GPS, biometrics, etc) Simulate user interaction events such as keypresses Create a trusted UI session Requires the SwEvent permission for interaction (Perform silent installation of packages)

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