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The Neuron/Silicon Interface Neuron survival and reorganization is paramount to long-term functional connectiv- ity with a microelectronic neural prosthetic implant buy discount propecia 1 mg on-line hair loss hereditary. The foreseeable challenges to the seamless integration of such a device center on the longevity of adhesion and sur- vival strategies cheap propecia 1mg line hair loss cure za. For a neural prosthetic implant to be e¤ective, its surface must be engineered to promote intimate contact with neural tissue while simultaneously avoiding activation of an inflamma- tory response. An integral part of achieving this is the development of surface coatings for the packaging materials, electrodes, and platforms. Ideally, the surface coatings will be tuned to the properties of each surface to match their function within the implant. One can anticipate that platform materials will include both rigid substrates, such as The Biotic/Abiotic Interface 223 Table 11. Requires coating with material used in multisite organic adhesion molecule (poly-d-lysine, electrode arrays) laminin, etc. Electrode materials will include simple metals, such as platinum or gold, as well as metal oxides and nitrides, such as iridium oxide (IrO2), indium tin oxide (ITO), and TiN. The packaging materials will include some of the same materials, that is, ceramics and glass, as well as other environmentally stable materials, such as titanium and stainless steel. The surface treatment chemistries being developed for controlling cell attachment and specific cell recognition must be e¤acious for each of these surfaces and be adaptable to new materials that we have not yet envisioned. Neuron/silicon interfaces will have to be tailored to the material requirements of the device. Next, these pro- cesses can be used to anchor groups chosen to carry out specific operative functions, including selective cell binding, cell repulsion, and controlled release of a substance (Mohajeri et al. Our previous work, as well as that of others in the field, indicates that selected sil- icon surfaces (table 11. Di¤erent substrates result in di¤erent neuron topographies (see table 11. Gold Excellent Neurons attach, adhere for an extended time; permits neuronal process outgrowth. Indium tin oxide No neuronal Thin-film transparent microelectrodes that permit (ITO) adhesion visualization of cells on top of microelectrodes. Platinum black No neuronal Requires coating with organic substrate for neuronal adhesion adhesion. Titanium nitride No neuronal Requires coating with organic substrate for neuronal adhesion adhesion. Microcolumnal shape results in low impedance (80–250 kW) and high charge-transfer capacity, which enables greater stimulation intensities. For example, the density of positive charges and polymer size dramatically a¤ects neuronal cluster development (see figure 11. Dissociated single neurons seeded onto 30,000–70,000 molecular weight polymers of poly-d-lysine and poly-d-ornithine substrates migrate to form small clusters, whereas neurons seeded onto polyethylenimine, which is more highly positively charged, do not migrate to form clusters and su¤er a higher degree of cell death. Inclusion of basement mem- brane, a complex extract of extracellular matrix from a mouse tumor cell line, with any of these substrates greatly increases the capacity of neurons to migrate into clus- ters (see figure 11. Poly-d-lysine and laminin are known to be particularly e¤ective in promoting ad- hesion of dissociated neuron cultures onto inorganic materials, and we investigated their e‰cacy with regard to our hippocampal conformal multisite electrode arrays (Soussou et al. Poly-d-lysine and laminin were applied to the surface of the conformal arrays, with application limited to linear tracks aligned with the long axis of each column of electrode sites in the rectangular array (figure 11. When dissociated hippocampal neurons were prepared on the surface of the array, the adhesion of cells and the extension of their processes were restricted to the treated regions. Neural networks that formed were predominantly in parallel, linear tracks over the columns of electrodes. The Biotic/Abiotic Interface 225 Poly-D-Lysine Substrate Poly-D-Lysine with Basement Membrane Matrix Figure 11. The panels on the far left show hippocampal neurons grown on glass coated with poly-d-lysine in the absence (top) and in combination with basement membrane matrix (bottom). Note that in the presence of basement membrane, neuronal clusters appear more frequently and a modest degree of process fasciculation occurs. The middle panels show phenotypic development of neuronal processes on these two substrates. Dendritic processes are la- beled with the dendrite selective marker MAP2 shown, while axons are labeled with the axon-selective marker, GAP43. In the third panel are dissociated hippocampal neurons cultured onto multisite electrode arrays. Note that in the presence of basement membrane, a much greater degree of clustering of neurons and fasciculation of their processes occurs. Polyornithine PO Structurally very similar to PDL, but (PO) H N H O unbranched cationic polymer, with peptide 2 bonds. NH CH2CH2CH2C C n Polyethyleneimine PEI Branched cationic polymer with no (PEI) CH2CH2NH2 carboxylic group, thus more positively NH CH CH N CH CH charged.

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As molds cheap 1 mg propecia visa hair loss post pregnancy, these fungi produce spores that immune defense mechanism of phagocytosis order propecia 1 mg without prescription hair loss in men running. Aspergillus can persist indefinitely in the environment and be carried by organisms produce protease, an enzyme that allows them to the wind to distant locations. When these mold spores enter the destroy structural proteins and penetrate body tissues. They have a thick, rigid cell wall, of which one of the com- human pathogens such as those that cause blastomycosis, ponents is a polysaccharide called glucan. Fungi also 595 596 SECTION 6 DRUGS USED TO TREAT INFECTIONS have a cell membrane composed of lipids, glycoproteins, and tochrome P450 enzyme (14-alpha demethylase) that is re- sterols. One of the sterols is ergosterol, a lipid that is similar to quired for synthesis of ergosterol from lanosterol, a precursor. Within This action causes production of a defective cell membrane, the cell membrane, structures are essentially the same as those which also allows leakage of intracellular contents and de- in human cells (eg, a nucleus, mitochondria, Golgi apparatus, struction of the cell. Both types of drugs also affect cholesterol ribosomes attached to endoplasmic reticulum, and a cyto- in human cell membranes, and this characteristic is considered skeleton with microtubules and filaments). Echinocandins or glucan synthesis inhibitors (eg, caspo- fungin) are a new class of antifungal drugs that disrupt fun- FUNGAL INFECTIONS gal cell walls rather than fungal cell membranes. They act by inhibiting beta-(1,3)-D-glucan synthetase, an enzyme re- Fungal infections (mycoses) may be mild and superficial or quired for synthesis of glucan. Dermatophytes cause superfi- saccharide in the fungal cell wall; its depletion leads to cial infections of the skin, hair, and nails. Drugs for superficial fungal infections of skin and mucous Most fungal infections occur in healthy people but are more membranes are usually applied topically. Patients with HIV infections (eg, oral, intestinal, or vaginal candidiasis) with anti- infection need aggressive treatment of primary fungal infec- bacterial drug therapy. In immunocompromised hosts, candi- tions and prolonged or lifelong secondary prophylaxis. Patients dal infections are more likely to be deep, widespread, and with prolonged or severe neutropenia secondary to treatment caused by non-albicans species. Instead, they of fungal infections, because they are at high risk for acute, grow in soil and decaying organic matter. Most invasive fungal life-threatening, systemic mycoses such as candidiasis and as- infections are acquired by inhalation of airborne spores from pergillosis. Selected antifungal drugs are further described in contaminated soil and severity of disease increases with inten- the following sections. Infections such as histoplasmosis, coccid- teristics of selected drugs are listed in Table 40–1; clinical in- ioidomycosis, and blastomycosis usually occur as pulmonary dications for use and dosage ranges are listed in Drugs at a disease but may be systemic. Serious, systemic fungal infections commonly occur and Polyenes are increasing in incidence, largely because of human immuno- deficiency virus (HIV) infections, the use of immunosup- Amphotericin B is active against most types of pathogenic pressant drugs to treat clients with cancer or organ transplants, fungi, including those that cause aspergillosis, blastomyco- the use of indwelling intravenous (IV) catheters for prolonged sis, candidiasis, coccidioidomycosis, cryptococcosis, histo- drug therapy or parenteral nutrition, implantation of pros- plasmosis, and sporotrichosis. The drug is fungicidal or thetic devices, and widespread use of broad-spectrum anti- fungistatic depending on the concentration in body fluids and bacterial drugs. Characteristics of selected fungal infections on the susceptibility of the causative fungus. The drug is usually given Antifungal Drugs for 4 to 12 weeks but may be needed longer by some clients. Lipid formulations were developed to decrease adverse Development of drugs that are effective against fungal cells effects, especially nephrotoxicity. Compared to the original without being excessively toxic to human cells has been lim- deoxycholate formulation (Fungizone), these mixtures of ited because fungal cells are very similar to human cells. At the same time, tic effects by disrupting the structure and function of various lipid formulations do not penetrate normal tissues well and fungal cell components (Fig. This Polyenes (eg, amphotericin B) and azoles (eg, flucona- decreases adverse effects and also allows higher doses to be zole) act on ergosterol to disrupt fungal cell membranes. Although these products cause much less nephrotoxi- photericin B (and nystatin) binds to ergosterol and forms city, chills, and fever, they are much more expensive than the holes in the membrane, causing leakage of the fungal cell deoxycholate formulation. The azole drugs bind to a cy- ommended for use only in clients who cannot tolerate the CHAPTER 40 ANTIFUNGAL DRUGS 597 BOX 40–1 SELECTED FUNGAL INFECTIONS Aspergillosis, the most common invasive mold infection world- other sources of infection. One recent study identified a hospital wide, occurs in debilitated and immunocompromised people, water system as a source of exposure. More airborne particles con- including those with leukemia, lymphoma, or acquired immuno- taining aspergillus were found in bathrooms than in patient rooms deficiency syndrome (AIDS), and those with neutropenia from a and hallways and A. The researchers concluded that the hos- velop in the bronchi, lungs, ear canal, skin, or mucous membranes pital water supply can be a source of nosocomial aspergillosis. It may extend into blood vessels, other study investigated the spread of invasive aspergillosis in an which leads to infection of the brain, heart, kidneys, and other or- intensive care unit for liver transplant patients. Invasive aspergillosis is a serious illness associated with veloped a wound infection 11 days after liver transplantation. Two thrombosis, ischemic infarction of involved tissues, and progres- other patients in the unit developed invasive pulmonary aspergillo- sive disease. The researchers concluded that Aspergillus organisms can form Allergic bronchopulmonary aspergillosis, an allergic reaction spores in infected wounds and that debriding and dressing those to inhaled aspergillus spores, may develop in people with asthma wounds may result in aerosolization of spores and airborne person- and cause bronchoconstriction, wheezing, dyspnea, cough, mus- to-person transmission.

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No shift was found 1mg propecia otc hair loss therapy cure power grow laser, surprisingly order propecia 5 mg mastercard hair loss alopecia, for the lem in sensorimotor integration in subjects wrist representation. An active and tent with other studies revealing that a discon- passive movement fMRI study and TMS pro- nected, but available cortical representation duced contralateral activation for the unaf- may come to cofunction with neighboring fected hand in seven subjects. Twelve subjects who had a mild TBI 1 month SPINAL CORD INJURY before testing were compared to controls in the Paraplegic and tetraplegic subjects reorganize auditory n-back task (see Experimental Case their primary sensorimotor cortical represen- Study 3–1) for assessing working memory (see tations for movements. Activity in the bilateral dorsolateral (Tower of London task), switching from one prefrontal and superior parietal cortices was aim to another during a task (Stroop Test), as- similar for the 0-back (simple vigilance) com- pects of memory,141,142 expectation and receipt pared to 1-back (low demand) condition. A of rewards,143 and emotional responses to stim- much more extensive activation was found in uli144 can be used to compare normal subjects these regions on the right in patients with TBI to people who remain disabled by the typical for the 1-back to 2-back comparison, although sequelae of TBI (see Chapter 11). Both groups had a lying hypothesis is that patients process infor- similar magnitude of task-related increase in mation less efficiently after TBI. In addition, activation when the 0-back and 2-back were the effects of repetition and priming on mem- compared. Functional imaging, then, revealed ory processing can be monitored by functional a difference in the ability of the TBI subjects imaging, which may aid the development of to modulate or allocate resources with an in- cognitive rehabilitation approaches. The clin- ical symptoms of the patients suggested diffi- MULTIPLE SCLEROSIS culties in the maintenance and manipulation of verbal information. A study of patients who The partial remissions after exacerbations of were recovering from more severe TBI used multiple sclerosis (MS) and the progression the paced auditory serial addition test to assess over long periods of time lead to the specula- working memory (see Chapter 7). Compared tion that partial restitution and substitution to healthy subjects, the patients made more er- may evolve from lesion-induced and practice- rors and the pattern of cerebral activations was related network and representational plasticity, more dispersed and lateralized to the right improved axonal conduction,146 remyelination, frontal lobe. By the same logic, exhaus- impaired network may require larger or more tion of reorganizational plasticity as the burden widespread network activity to successfully of axonal lesions grows may contribute to func- carry out cognitive tasks. Another PET activation study examined one An fMRI study employed simultaneous flex- of the consequences of diffuse axonal injury. Perseverative errors were higher ipsilateral activation accompanied significantly and inversely related to metabo- greater functional impairment in patients com- lism in the right, but not the left dorsolateral pared to controls. This re- weighted MRI lesion load of MS plaques, the lationship was independent of any individual center of the activation shifted posteriorly in differences in global brain metabolism, general the sensorimotor representation contralateral cognitive ability, or overall performance on the to the hand that moved, especially as the vol- test. No relationship was found between per- ume of the MS lesions increased within the severative errors and the presence of prefrontal corticospinal projection. Functional imaging tests of tion moved approximately 8 mm, from the pos- this frontal-subcortical circuit, then, may help terior wall of the precentral gyrus to the ante- clinicians measure the impact of diffuse axonal rior wall of the postcentral gyrus in 15 of 24 injury in frontal white matter and serve as phys- subjects. As in the studies of patients with iologic markers for the evaluation of cognitive stroke described earlier, this posterior migra- and pharmacologic interventions aimed at tion may point to a greater representational modulating the circuit. A study of 176 Neuroscientific Foundations for Rehabilitation patients with primary progressive MS who had sentational changes as assessed by TMS, MEG, normal function of an upper extremity also re- PET, and fMRI. Transcranial magnetic stimu- vealed a different pattern of cortical activation lation reveals a lower threshold, greater num- than healthy control subjects during flexion- ber of stimulation sites, and higher evoked am- extension movements of the unaffected plitude for the muscles most proximal to the hand. In addition, functional imaging TRAINING-INDUCED has revealed evidence for motor reorganization REORGANIZATION after a single bout of MS148a and adaptive changes during a sustained attention task in pa- Although the number of pilot studies of pa- tients who performed normally. Nine patients with CADASIL, for The ideal serial study compares perform- example, were more likely to have bilateral ance-related activations before, during, and af- S1M1 activations on an fMRI task of hand tap- ter completion of training. For example, if a by MR spectroscopy, the ipsilateral activation patient practices repetitive functional use of the increased. Fatigue may be and may include preforming the hand in the associated with impaired functionality between shape of the item to be grasped. The success of cortical and subcortical components of a net- training ought to be measured by tools that are work in patients with MS (see Chapter 12). Thus, disruption of corticosubcorti- achieve an important behavioral milestone or cal circuits is associated with central fatigue. Color Figure 3–8 (in separate color insert) shows the consequences of this strategy. Learning- Peripheral Nerve Transection dependent plasticity is a function of the inten- sity, duration, and specificity of what is prac- Experimental studies in monkeys that had a ticed (see Chapters 1 and 2). This investigational strategy allows the muscle was smaller than in the unaffected clinician to study patients at any point in time hand. Behavioral outcomes for the upper ex- after onset of a persisting impairment and dis- tremity significantly improved with training. The critical component is the need for The gains were associated with an expansion of a well-defined and testable rehabilitative in- the scalp areas that evoked a thumb muscle re- tervention. Indeed, after one day of therapy, stim- gators to use functional neuroimaging as a ulation sites over the infarcted hemisphere physiologic marker of the adequacy of inter- changed from about 40% less than those on the ventions for rehabilitation. For example, a poor resentational plasticity suggests that much la- performance in discriminating the size of ob- tent function of the hand had been present.

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