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  • Professor, Neurology UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA

https://profiles.ucsf.edu/william.weiss

The standard lexical–semantic and grapheme–phoneme conversion Speech production routes are shown in green and red respectively generic 100 mg addyi overnight delivery. The lexical–semantic route is faster and can read Impaired Spared = Phonological dyslexia all known words (whether regular or irregularly spelled) Spared Impaired = Surface dyslexia but is more ef cient for common discount addyi 100 mg otc, high-frequency words cheap addyi 100 mg line. Within the original dual 80 route model generic addyi 100 mg, this was explained as damage to grapheme–phoneme conversion and use of the 60 intact semantic pathway (Marshall & Newcombe, 1973). However, this explanation is clearly in 40 adequate, because it predicts that the semantic route is normally very error-prone in us all, and 20 it fails to predict that patients with deep dyslexia have comprehension problems on tests of seman 0 0–2 3–9 10-19 20-39 40-99 100+ tic memory that do not involve written material (Shallice, 1988). The most common way of ex Word frequency plaining deep dyslexia is to assume that both High frequency + regular High frequency + irregular reading routes are impaired (Nolan & Caramazza. The lexical–semantic route is degraded charge sure such that similar concepts have effectively be Low frequency + regular Low frequency + irregular come fused together and cannot be distinguished. Frequency > regularity interaction in the word reading of a A number of studies have reported patients semantic dementia patient and examples of words falling into who can read words aloud accurately but have these categories. The problem with nonwords implies a dif culty in grapheme–phoneme conversion, and the problem in comprehension and semantic memory implies a dif culty in the lexical–semantic route. To accommodate these data, several researchers have argued in favor of a “third route” that links the visual lexicon with the phonological lexicon but does not go through semantics (Cipolotti & Warrington, 1995b; Coltheart et al. There are several alternative accounts to the “third route” that have been put forward to explain good word reading in the face of impaired semantic knowledge. They suggest that an intact semantic system is always needed for reading these words, but people differ in the extent to which they rely on one route more than the other. Those who rely more on the semantic route before brain damage will show the largest disruption in reading ability when they go on to develop semantic dementia. An alternative to the third route is provided by the summation hypothesis (Hillis & Caramazza, 1991; Ciaghi et al. The summation hypothesis states that lexical representations in reading are selected by summing the activation from the semantic system and from grapheme–phoneme conversion. Thus patients with partial damage to one or both of these routes may still be able to achieve relatively pro cient performance at reading, even with irregular words. However, the grapheme–phoneme conversion system will also activate, to differing, a set of lexical can didates that are phonologically similar (“beer,” Letter recognition “bare,” “bar,” etc. By combining these two sources of information, the patient should be able to arrive at the correct pronunciation of “bear,” even though neither route may be able to select the Visual (input) correct entry by itself. Their surface Grapheme–phoneme dyslexic/dysgraphic participant was able to read conversion and spell irregular words for which he had partial Semantic “Third Phonological (output) lexicon What has functional imaging revealed about the existence of multiple routes Speech production processes the initial motivation for postulating two (or more) routes for reading was cognitive, not neuroanatomical. Nevertheless, functional imag Impaired Spared = Phonological dyslexia ing may provide an important source of con Spared Impaired = Surface dyslexia verging evidence to this debate—at least in Impaired Impaired = Deep dyslexia principle (for reviews, see Fiez & Petersen, 1998; Jobard et al. Of An adapted dual-route model of reading showing two alternative course, functional imaging measures the activity modi cations to the model (blue lines). These modi cations have of regions only in response to particular task been proposed by some researchers to account for the fact that demands, and so it does not provide any direct some acquired dyslexic patients can read irregular words that evidence for actual anatomical routes between they cannot understand. These include the inferior frontal cortex (including Broca’s area); the inferior parietal lobe; and several anterior and mid-temporal lobe regions. Some have suggested that the inferior frontal lobe does not have a core role to play in single-word reading, but is instead related to general task dif culty (Cattinelli et al. However, others have suggested that it has a speci c role in converting graphemes to phonemes (Fiebach et al. An Grapheme–phoneme alternative way of interpreting increased activity Conversion for low frequency irregular words is by assuming It is possible that both claims could be true if different sub-regions were contributing to both reading routes. Patients with damage to the wider Key areas identi ed in brain imaging studies and their possible functions. Note that the anatomical routes (and intermediate inferior frontal region make more errors on non processing stages) are largely unknown and are shown here as words than real regular words, but additionally illustrative possibilities. The role of the inferior frontal lobe struggle with low-frequency irregular words (Broca’s area) in reading is uncertain but may contribute to both (Fiez et al. That is, the pattern is neither a semantically based reading and reading via phonological speci c pro le of surface dyslexia or of phono decoding. It may also bias the reading strategy that is adopted logical dyslexia but a mix of the two. Inferior parietal lobe the inferior parietal lobe consists of two anatomical regions: the supramarginal gyrus, which abuts the superior temporal lobes; and the angular gyrus, lying more posteriorly. The supramarginal gyrus was historically linked to Wernicke’s area (and phonological processing in particular). With particular reference to reading, it has been suggested that the left supramarginal gyrus is implicated in grapheme–phoneme conversion. These ndings suggest piecemeal processing of letter string rather than holistic recognition. Finally, patients with semantic dementia hyper-activate this region, relative to controls, when attempting to read low frequency irregular words (Wilson et al.

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Maximum functonal recovery is achieved with an optmal cooling rate providing reversible dehydraton occurring over the high subzero temperature range 100mg addyi. If cooling is too slow purchase addyi 100mg with mastercard, irreversible injurious dehydraton can take place addyi 100mg on line, for example the mitochondria and endoplasmic retculum are structurally compromised buy 100mg addyi overnight delivery. If cooling is too fast, cells do not have tme to optmally dehydrate, and residual intracellular water can form ice, which is again injurious and can compromise structure of organelles. For many nucleated mammalian cells, ‘optmal’ cooling equates to rates of around 1 C min. This tempera The question then arises as to what ture range relates to the total solute the desired end temperature should concentration of the mixture, but be for success, and the requirement for all practical purposes in cell ther for temperature control over that apy the quoted fgures are relevant. It has now been established It has been established empirically from a number of studies that for in diferent systems however, that true long-term stability, temperatures practical benefts for slow cooling be below 100oC become essential [27]. Tereafter, the becomes so highly viscous that the samples can be cooled below the glass glass transition event (Tg) becomes transition to close to the storage tem highly probable on further cooling. A schematic (but still controlled) rates of about of a slow cooling process is provided 10o or 20oC min-1 [29]. The mixture is cooled (red line) down to the ice nucleaton temperature (ofen around 7 C) and ice nucleaton startso (white icons). A hold tme (approximately 10 minutes depending on sample) can be introduced to allow dissipaton of latent heat which may confound cooling control. Thereafer, slow controlled cooling produces responsive dehydraton as ice crystal volume grows. This beneft of this is maximized by reaching approximately 50 C, and thereafero the sample can be cooled to below the glassy transiton range (approx. The cryopreserved sample thus comprises biomass (orange) and glassy matrix (grey blocks), mixed with ice already present. For each cell ble cryogenic temperatures (below therapy, the ease of application for 150oC) that can be obtained (with storage at 80oC needs to be bal modern storage containers ftted anced by an understanding of prod with appropriate monitoring and uct stability. The advent of electrical if needed, autofll devices) are suf freezers operating in the 120oC fciently far enough below the glass range has opened this possibility as transition range to yield true long a storage temperature for cell ther term biopreservation on a scale apies, which is predicted to have probably greater than required for successfully long storage times, but most cell therapies. It has been often little published information on that discussed that below Tg and in the is currently available for prospective highly viscous environment, there studies comparing these technolo is insufcient thermal energy for gies with liquid nitrogen storage. The only storage below Tg, the occasional potential harmful process to impact report on negative efects of storage cryogenic storage has been suggest duration [37] are difcult to under ed to be background ionising radia stand on a physico-chemical basis. In temperature if cryogen levels are al practical terms, there have been lowed to vary widely. Repeated tem from above discussions that storage perature cycling through the range above Tg is likely to result in slow for Tg in this fashion led to a de but progressive cryo-attrition. It has been alternative peratures usually in the region of ly argued that slow warming may 150o to 170oC) is attractive, but be benefcial to allow time for os potentially capable of rapid tem motic re-equilibration processes perature fuxes such as when open to take place [25] when the highly ing the storage container. Happily, shrunken cells start to encounter the placement of commonly used more liquid water as the ice matrix aluminium racks within the storage melts at high subzero temperatures. As in Consideratons for warming cooling, terms such as ‘fast’ or ‘slow’ For successful recovery of potent warming are relative and should be cell therapies, the reversal of all the defned in any cell therapy protocol above described biophysical events for process repeatability. For the Cryopreservaton and cell most part, cell therapies are tradi product potency tionally subject to cooling, in the In many cases, the potency of thawed presence of signifcant ice content cell therapies may not equate to in the sample. It has long been rec what might be predicted from the ognised that during the warming doses selected for cryopreservation. In addi after rewarming in a process known tion, if small intracellular ice nuclei as ‘cryopreservation cap’ or ‘cryo were established during the cool preservation-induced delayed onset ing process, but did not grow to cell death’ [45,46]. Cell death path become injurious, these may grow ways such as apoptosis and necrosis during warming, again depending have been identifed. Tere appears on the kinetics of warming, such to be a progression of expressed that ‘freezing during thawing’ can injury over the frst 12–24 h post be conceptualised [42]. Target Cryogenic preservaton ed molecular strategies have been in the absence of ice: suggested to mitigate against these vitrifcaton injuries [47] but for clinical applica The concept that biological cryo tion these need to be regulatory ap preservation could be achieved proved strategies. Tese post-thaw by avoiding ice injury with pro injury markers also ofer one way cesses that entirely inhibit crystal to audit efectiveness of cryopreser growth has been considered for vation protocols or assess protocol many years; the original paper by change. In practcal cell cryopreservaton by slow cooling, ice plus glassy matrix co-exist beyond approximately 120 C. For ultra-rapid cooling (lef side box, red), amorphous matrix is preserved from above 0 C throughout the cooling, at rates greater than 1000 C min to reach Tg (dashed red curve) but this tendso o 1 to be metastable with similar problems of devitrifcaton on warming. The fgure is a simplifcaton of events for visual presentaton; for details see Muldrew (2004), Fahy & Wowk (2015). Later, of a cell therapy product which Rall and Fay were able to translate has been applied widely since the the ideas into an achievable tech 1960s [52,53]. Miltenyi Biotec or Maco ing and warming (which in turn Pharma) with a range of fll volumes limits the volumes used to <1 ml). Recent tered the arena within the broad studies have been made into devel area of hematopoietic stem cell opment of vitrifcation technolo replacement, slow cooling cryo gies compatible with large volumes preservation has maintained its (see Puschmann et al [51] for a re benefcial role, but with some ad view), but these have yet to be ap dition to detail in terms of protocol plied to deliverable cell therapies. Tere have been gous transfusion [64,65], cryopreser several reports of mesenchymal vation will undoubtedly remain the stromal cells for expansion and important facilitatory technology in cryopreservation for clinical appli the pathways for product manage cations, such as in graft versus host ment, batch safety and potency val disease [60], but the product poten idation, and, in many cases, deliv cy has come into question [61] and ery to end users. Cryopreservation cryopreservation was one of the has already been discussed in these steps under scrutiny. Other Post-thaw culture for 24 h was manipulated allogeneic immune cell found to be efective in reparation therapies (such as natural killer cell of many of the cryo-induced abnor or regulatory T-lymphocyte thera malities. Tere practices which were reported un is an opportunity for much further der the umbrella term ‘cryopreser work on fundamental cryobiology vation’ [63]. In the short ities; this is that cryopreservation is term, it may be possible to mitigate not a simple ‘standardised one op against loss of potency post-thaw tion’ process, the various protocol by adjusting dose (delivered cell steps need to be well documented numbers) but this still leaves dif in standard operating procedures, cult questions if the impact of cryo and the equipment involved should preservation on the therapeutic cell be applied with care and monitored population is not fully understood, frequently against documented per and which may therefore vary be formance criteria. Other types of in fact that optimal cryo-dehydration organic ice nucleating surfaces are is essential for cell survival, which under development [IceStart™, As is achieved by the osmotic efects ymptote]. Another problem with of the growing ice content in the cryopreservation of large samples is sample.

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At other times generic 100mg addyi overnight delivery, bacteria or fungi from a contaminated contact lens can pass into the cornea buy addyi 100 mg without prescription. Situations like these can cause painful inflammation and corneal infections called keratitis discount 100mg addyi. These infections can reduce visual clarity purchase addyi 100mg otc, produce corneal discharges, and perhaps erode the cornea. Corneal infections can also lead to corneal scarring, which can impair vision and may require a corneal transplant. As a general rule, the deeper the corneal infection, the more severe the symptoms and complications. It should be noted that corneal infections, although relatively infrequent, are the most serious complication of contact lens wear. If the problem is severe, it may require more intensive antibiotic or anti-fungal treatment to eliminate the infection, as well as steroid eye drops to reduce inflammation. Frequent visits to an eye care professional may be necessary for several months to eliminate the problem. In people with dry eye, the eye produces fewer or less quality tears and is unable to keep its surface lubricated and comfortable. The tear film consists of three layers an outer, oily (lipid) layer that keeps tears from evaporating too quickly and helps tears remain on the eye; a middle (aqueous) layer that nourishes the cornea and conjunctiva; and a bottom (mucin) layer that helps to spread the aqueous layer across the eye to ensure that the eye remains wet. Also, in some cases, the lipid and mucin layers produced by the eye are of such poor quality that tears cannot remain in the eye long enough to keep the eye sufficiently lubricated. The main symptom of dry eye is usually a scratchy or sandy feeling as if something is in the eye. Other symptoms may include stinging or burning of the eye; episodes of excess tearing that follow periods of very dry sensation; a stringy discharge from the eye; and pain and redness of the eye. Sometimes people with dry eye experience heaviness of the eyelids or blurred, changing, or decreased vision, although loss of vision is uncommon. This is because the eye may be producing less of the lipid and mucin layers of the tear film, which help keep tears in the eye. When this happens, tears do not stay in the eye long enough to thoroughly moisten it. Dry eye can occur in climates with dry air, as well as with the use of some drugs, including antihistamines, nasal decongestants, tranquilizers, and anti-depressant drugs. People with dry eye should let their health care providers know all the medications they are taking, since some of them may intensify dry eye symptoms. People with connective tissue diseases, such as rheumatoid arthritis, can also develop dry eye. Artificial tears, which lubricate the eye, are the principal treatment for dry eye. Sterile ointments are sometimes used at night to help prevent the eye from drying. Using humidifiers, wearing wrap-around glasses when outside, and avoiding outside windy and dry conditions may bring relief. For people with severe cases of dry eye, temporary or permanent closure of the tear drain (small openings at the inner corner of the eyelids where tears drain from the eye) may be helpful. As more endothelial cells are lost over the years, the endothelium becomes less efficient at pumping water out of the stroma. Eventually, the epithelium also takes on water, resulting in pain and severe visual impairment. This occurs because the cornea is normally thicker in the morning; it retains fluids during sleep that evaporate in the tear film while we are awake. As the disease worsens, this swelling will remain constant and reduce vision throughout the day. When treating the disease, doctors will try first to reduce the swelling with drops, ointments, or soft contact lenses. When the disease interferes with daily activities, a person may need to consider having a corneal transplant to restore sight. However, some studies suggest that the long-term survival of the new cornea can be a problem. Corneal Dystrophies A corneal dystrophy is a condition in which one or more parts of the cornea lose their normal clarity due to a buildup of cloudy material. Most usually begin in one of the five corneal layers and may later spread to nearby layers. Most do not affect other parts of the body, nor are they related to diseases affecting other parts of the eye or body. Some cause severe visual impairment, while a few cause no vision problems and are discovered during a routine eye examination. Other dystrophies may cause repeated episodes of pain without leading to permanent loss of vision. This infection is produced by the varicella-zoster virus, the same virus that causes chickenpox. After an initial outbreak of chickenpox (often during childhood), the virus remains inactive within the nerve cells of the central nervous system. But in some people, the varicella-zoster virus will reactivate at another time in their lives.

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