Andrew Chan, MD

• Resident, Neurological Surgery, University of California, San Francisco, San Francisco, CA

https://profiles.ucsf.edu/andrew.chan

Postoperatively the patient is provided with a sling for comfort but immediate active mobilization is initiated with the patient lying supine and the shoulder flexed to 90 degrees allergy nyc effective allegra 120mg. The use of a splint or cast is not recommended and passive stretch should be avoided allergy symptoms loss of voice generic allegra 120mg free shipping. Despite these measures the patient often does not regain full extension and they should be counselled accordingly before surgery allergy symptoms skin rash discount allegra 120 mg. A description of this sort fails to convey the real difficulty of these operations allergy and immunology fellowship discount 120mg allegra otc, which can provide a real challenge even in the most skilled hands allergy zucchini symptoms buy allegra 120mg free shipping. Elbow hemiarthroplasty Replacement of the distal humerus alone is finding an increasing role for the treatment of very comminuted fractures in elderly osteoporotic patients as it avoids additional surgery to the ulna allergy symptoms chills order allegra 180 mg fast delivery, the part of a total elbow replacement that tends to fail first. Total elbow replacement Total joint replacement is an option for unreconstructable distal humerus fractures and in particular those with pre-existing joint disease. An excellent reduction was obtained in this case; however, the elbow sometimes ends up with considerable loss of movement even though the general anatomy has been restored. Active range of movement exercises are started as soon as tolerated and continued until gains in range of movement have plateaued. In children radial neck fractures are more common because the head is largely cartilaginous. Radial head fractures may be isolated bony injuries or part of a pattern of fracture dislocation of the elbow, which will be dealt with separately later. The injury may be associated with lateral ligament avulsion and/or medial ligament tear. Vigilance is required to make the diagnosis and institute treatment as early as possible. Nerve injury this is most commonly to the ulnar nerve but the radial nerve may be injured by a long lateral plate and median nerve injury has been reported. It is important to examine the hand and record the findings before any treatment is commenced. The most reliable predictor of elbow instability is loss of cortical contact of the radial head fragment(s). The causes of elbow stiffness may be intrinsic (intra-articular adhesions, capsular contracture, joint incongruity, instability) or extrinsic (heterotopic ossification or nerve entrapment). Prevention is the best management plan with early restoration of skeletal stability and early active mobilization and avoidance of painful passive stretch. For those patients who develop a very stiff elbow with unacceptable function, elbow arthrolysis may be indicated. The success of this procedure is dependent on establishing the cause of the stiffness and addressing this directly. Most will regain a pain-free elbow with only a slight loss of extension the most common sequel. Aspiration of the haematoma from the elbow joint and injection of local anaesthetic may provide relief of initial pain but may also increase the risk of infection. In some cases, despite surgical reconstruction, the elbow is still not stable and an external fixator may have to be applied across the elbow to maintain acceptable alignment. Assessment of those with loss of forearm rotation can be a challenge; is there truly a mechanical block or is there simply too much pain to permit movement Aspiration and local anaesthetic injection can be used but gentle assessment of passive range of movement or reassessment at 1 week with repeat clinical examination may provide useful information. Loss of cortical contact of the radial head fragment or a fragment that is greater than a quarter of the radial head surface can be associated with instability of the elbow. In all surgical cases the associated soft-tissue injury (lateral ligament avulsion) should be addressed with suture anchor repair back to the humerus. The treatment is usually surgical, with radial head fixation or replacement and lateral ligament repair. Coronoid fixation is required only if the fracture extends to the medial facet, and opinion varies about repair of the medial ligament. In many cases non-operative management will result in rapid progression to osteoarthritis. Treatment consists of lateral ligament repair with or without fixation of the coronoid fragment, depending on its size. Monteggia fracture-dislocation is a proximal ulna fracture with dislocation of the radial head from the radiocapitellar joint. These can be divided into those with an apex anterior ulna fracture and those with an apex posterior ulna fracture. Apex anterior fractures carry a better prognosis because the radial head is often intact. In apex posterior fractures the radial head is driven into the capitellum, resulting in a comminuted radial head fracture that may be associated with coronoid fracture and ligament injury. This rare injury is associated with rupture of the central condensation of the interosseous membrane of the forearm, which should be addressed to produce a satisfactory outcome. The head must be meticulously reconstructed with small headless screws or replaced. Complications Joint stiffness is common and may involve both the elbow and the radioulnar joints. Even with minimally displaced fractures the elbow can take several months to recover, and stiffness may occur. Heterotopic ossification is an occasional complication that can result in dramatic stiffness. A double arc sign (two crescent shapes on the lateral view) indicates that the fracture extends into the trochlea, which is a more unstable situation than an isolated capitellum fracture. If undisplaced, non-operative management can produce acceptable results despite a relatively high rate of non-union. Treatment Undisplaced fractures are rare and can be treated with analgesia and a collar and cuff. While closed reduction is feasible, prolonged immobilization may result in a stiff elbow and therefore open reduction and internal fixation is preferred. If there is no dorsal comminution and good quality bone, one or two headless screws or lag screws can be passed from anterior to posterior to stabilize the fragment. If there is comminution, a dorsal lateral plate can be used with or without a block bone graft, depending on the amount of bone loss. Clinical features the elbow is typically held at around 70 degrees of flexion as this is the most relaxed position of the joint capsule accommodating the haemarthrosis. Bruising on the lateral side of the elbow indicates disruption of the superficial fascia and usually indicates a more significant soft-tissue injury. These can be further sub-classified into Imaging In the lateral X-ray view the capitellum is displaced such that the radial head no longer articulates 777 3 Type 1 undisplaced transverse fractures the triceps aponeurosis sometimes remains intact, in which case the fracture fragments stay together. A gap may be palpable and the patient will be unable to extend the elbow against resistance. The clinician should be alerted to the possibility of a stress fracture by an absence of these clinical signs and a history of prodromal pain. Note should be made of the fracture pattern, the presence of comminution, the degree of displacement and in particular signs of subluxation of the ulnohumeral joint or radiocapitellar joint. The fracture always enters the elbow joint and therefore may damage the articular cartilage. With In the elderly or infirm many of these fractures can be treated with analgesia and mobilization with a satisfactory outcome. An undisplaced transverse fracture that does not separate when the elbow is X-rayed in flexion can be treated without surgery. Anatomy the elbow is a complex hinge, providing sufficient mobility to permit the upper limb to reach through wide ranges of flexion, extension and (in conjunction with the forearm joint) rotation. Yet it must also provide enough stability to support the necessary gripping, pushing, pulling and carrying activities of daily life. The surrounding soft-tissue structures also are important, especially the capsular and collateral ligaments and, to a lesser extent, the muscles. When the elbow is flexed, the forearm comes to lie directly upon the upper arm (screw axis of rotation). Doubts about the normality of these features can usually be resolved by comparing the injured with the opposite arm. With the elbow flexed, the tips of the medial and lateral epicondyles and the olecranon prominence form an isosceles triangle; with the elbow extended, they lie transversely in line with each other. If elbow function is good, it can be ignored; if not, rigid internal fixation and bone grafting will be needed. Osteoarthritis this can be a late complication, especially if reduction is less than perfect. A simple dislocation is one without a fracture (although flake avulsions at the ligament insertions may be seen). In over 90% of cases the forearm dislocates in a posterior direction relative to the humerus. Mechanism of injury and pathology the majority of dislocations occur as a result of a fall on an outstretched hand with the elbow in extension often with a valgus force. It is not known what the risk factors are but they are likely to be related to associated avulsion of the humeral attachments of the secondary stabilizers of the elbow, i. If there are other signs of ischaemia, the injury should be treated as an emergency. If there is no improvement, an arteriogram is performed; the brachial artery may have to be explored by an appropriately trained surgeon. The bony landmarks (olecranon and epicondyles) may be palpable and abnormally placed. However, in severe injuries the pain and swelling are so marked that examination of the elbow is impossible. After the reduction, the elbow should be put through a full range of motion to see whether it is stable. The distal nerves and circulation are checked again and an X-ray is obtained to confirm that the joint is reduced. After 1 week the patient gently moves the elbow while lying supine with the shoulder flexed to 90 degrees and the forearm in neutral rotation. Often the clinician deciding on definitive treatment is not the one who performed the reduction and scant information is likely to be available about the elbow stability. If the soft-tissue injury extends into the lateral structures, there may be a role for examination under anaesthesia and open stabilization of the elbow. Stiffness Loss of 20-30 degrees of extension is not uncommon after elbow dislocation; fortunately, this is usually of little functional significance, although the patient may not be happy with the cosmetic impact and should be warned that this is a possibility. In the management of all elbow injuries the joint should be moved as soon as possible, with due consideration to stability of the fractures and soft tissues and without undue passive stretching. The use of a hinged brace, designed to control movement, may contribute to stiffness. Hypertonia of biceps and brachioradialis after injury or surgery will limit active extension. Mobilization with the patient lying supine, the shoulder flexed to 90 degrees and the arm supported by the other hand relaxes the muscles and provides gravitational stability of the ulna on the end of the humerus. Surgical intervention should not be rushed as the range of movement may improve up to 6 months from the time of injury. Heterotopic ossification this may occur in the damaged soft tissues in front of the joint. The precise pathogenesis is unknown but the risk is increased by associated head injury and by delay to surgical intervention. The clinician should be alert to the possibility in patients who fail to recover movement after injury or surgery. X-ray examination may be unhelpful initially; soft-tissue ossification is not usually visible until 4-6 weeks after injury. Anti-inflammatory drugs may help to reduce stiffness and can be used as prophylaxis against the formation of heterotopic ossification, but these are contraindicated while fracture healing is ongoing. Historically it was usual practice to wait for the ossification to mature but the evidence base does not support this. Recurrent dislocation the most common recurrent dislocation is posterolateral rotatory instability due to incompetence of the lateral ligament complex (discussed in Chapter 14). Recurrent ulnohumeral dislocation is rare but may follow simple elbow dislocation and will usually require reconstruction of the lateral ligament complex and possibly the anterior band of the medial ligament too. Instability after neglected fracture-dislocation can occur and may require reconstruction of ligaments and reconstruction or replacement of the radial head. Coronoid reconstruction is required rarely for chronic posteromedial rotatory instability. Osteoarthritis Secondary osteoarthritis is quite common after severe fracture-dislocations. Unreduced dislocation this is a very challenging problem to address because the joint fills with dense scar tissue, preventing reduction. Open reduction requires extensive soft-tissue release and ligament reconstruction with the use of an external fixator if the elbow remains unstable. Obviously, epiphyseal displacements will not be detectable on X-rays before these ages but soft-tissue swelling may be apparent on X-rays and should raise suspicion of an underlying fracture. Mechanism of injury Posterior angulation or displacement (95% of cases) suggests a hyperextension injury, usually due to a fall on the outstretched hand. The distal fragment is pushed backwards and (because the forearm is usually pronated) twists inwards.

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Arachnoid maldevelopment and ineffective communication between the cyst and the subarachnoid space are involved in the pathophysiology of arachnoid cysts [8] allergy symptoms and treatment buy 180mg allegra visa. The actual site or sites of communication may not always be evident because the magnitude of the flow may be below the detection sensitivity of the pulsing sequence or it may not lie within the imaged section allergic pink eye order allegra now. Its medial wall variably communicates with the basal cisterns allergy symptoms pineapple generic allegra 120 mg on line, either through a patent flow entry zone or through tiny perforations allergy shots mechanism discount allegra amex. The slit opens and closes during the cardiac cycle enabling fluid to fill and flush the cyst allergy symptoms hay fever order allegra toronto. It is traditionally assumed that the arterial pulse conducts the energy allergy zinc oxide purchase allegra cheap online, acting as the pump especially if closely surrounded by arachnoid adhesion [13]. Sudden contraction of the artery pulls the arachnoid attached to it, but the movement of the arachnoid itself is not so impetuous. Hence, during this interval, fluid moves conceivably following a pressure gradient. The arterial inflow has been considered inefficient to mediate a pump-like mechanism after having observed that the intracranial arterial diameter scarcely increases during systole. The slit (arrow) in the arachnoid next to the basilar artery opens during arterial inflow (A) and closes during basilar contraction (B). Williams and Guthkelch emphasized the sensitivity of the subarachnoid space to changes in venous pressure [5]. Whether by arterial or venous mechanism, these functional features support the existence of an anatomical communication between the subarachnoid space and the cyst. On the other hand, it has also been argued that Valsalva maneuvers can produce sufficient force to tear the arachnoid accelerating a natural decompression [14]. Accordingly, symptomatic cysts of suprasellar location have been mainly reported in childhood [15]. It has been reported only in suprasellar arachnoid cysts, and any study has identified neither radiological nor endoscopical observations in other locations [15]. Regardless of location, arachnoid cysts seem to behave similarly: they result from a developmental abnormality in the arachnoid membrane; frequently they are discovered incidentally; and most arachnoid cysts are quiescent and remain stable throughout life. From the requirement to explain these similarities emerges the necessity of determining a unified theory. The slit-valve mechanism does not satisfy it since it has been only observed, as aforementioned, in suprasellar arachnoid cysts. Although intra- and extracavitary components of arachnoid cysts have been defined as similar, ultrastructural analyses reveal that these differences are not minor. Therefore, there is morphological and ultrastructural evidence to support the secretory nature of the cyst wall. However, all these findings have been observed in temporal arachnoid cysts, and it is bias to extrapolate them to the whole entity. This would indicate that arachnoid cysts represent a heterogeneous group of pathological conditions and, presumably, different pathophysiological enlargement mechanisms. Arachnoid cysts: entrapped collections of cerebrospinal fluid variably communicating with the subarachnoid space. Value of phase contrast magnetic resonance imaging for investigation of cerebral hydrodynamics. Endoscopic observation of a slit-valve mechanism in a suprasellar prepontine arachnoid cyst: case report. Mechanical aspects of the cerebrospinal fluid circulationphysiological, pathological, surgical. Arachnoid cysts do not contain cerebrospinal fluid: a comparative chemical analysis of arachnoid cyst fluid and cerebrospinal fluid in adults. Congenital, genetic, and traumatic factors have been suggested as the underlying mechanisms [1]. This can be accompanied by atrophy of the adjacent cerebral tissue or can cause a mass effect. Their sample was hospitalbased patients that were recruited from a single university medical center. Their sample was highly selected and was composed of healthy young men who applied for the flying service in the German military [4]. The Rotterdam study was conducted to determine the prevalence of incidental findings in the general population [5]. Morris and colleagues reported in a systematic review and metaanalysis on incidental findings on brain magnetic resonance imaging [7]. It evaluated types and prevalence of all, incidental, and clinically relevant incidental intracranial findings, i. The sample comprised a population-based cohort (n 5 1235) aged older than 70 years. The raw mean prevalence treats each of the 10 studies equally, whereas the effect models use weighted averages of the individual study effect, the weights being inversely proportional to the within study variances. The fixed effects model assumes to estimate a true single effect size (prevalence), the random effects model assumes the prevalence of each study to have been sampled from a distribution of prevalences. There is strong evidence for heterogeneity (Q 5 468) between the 10 studies, reflecting their different origins. The categorization differs between the studies, leaving a substantial proportion of "other" locations (Table 9. The next most frequent location is the posterior fossa with about one-third of all cysts. In the frontal and in the parietotemporal regions are in each case about 7%, and the rest (5%) elsewhere. Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis. Incidental findings on computed tomography scans in children with mild headtrauma. A population-based study of intracranial arachnoid cystsClinical and radiological outcome following surgical cyst decompression in adults. Surgical management strategies of intracranial arachnoid cysts: a single institution experience of 75 cases. Based on 208 reported cases in the literature, Rengachary and Wantanabe found the following distribution in their pioneer study from 1981: Sylvian fissure 103 (49%), cerebellopontine angle 22 (11%), supracollicular area 21 (10%), vermian area 19 (9%), sellar and suprasellar area 18 (9%), interhemispheric fissure 10 (5%), cerebral convexity 9 (4%), and clival area 6 (3%) [1]. In a population-based patient material from our institution, the intracranial distribution among 299 patients with 305 cysts (six patients with bitemporal cysts) was as follows: the vast majority-198 patients (66. In the same population, cysts in the middle fossa demonstrated a significant preponderance for the left side in both genders. A similar significant sidedness was found for cysts located in the cerebellopontine angle, although on the right side [2]. It has well-defined margins, and the cyst wall does not enhance after intravenous contrast injection. The lesion is small, spindle-shaped, and limited to the anterior aspect of the temporal fossa. It occupies the anterior and middle part of the temporal fossa and extends superiorly along the sylvian fissure, which is therefore widely open with the insula exposed. A mass effect, though not particularly severe, was seen in more than half of the patients. Cranial deformities on plain radiograms and angiographic abnormalities were constantly detectable, but sometimes of a moderate degree. Drainage of contrast from the lesion was delayed compared with type I cysts and the subarachnoid space. It occupies the temporal fossa almost entirely and extends over a wide area of the cerebral hemispheres, splitting the opercula of the sylvian fissure. The temporal lobe is severely atrophic and both the frontal and parietal lobes are extensively compressed, so that a large part of the one side of the cranial cavity may be occupied. The ventricles and midline structures are noticeably and sometimes tremendously distorted and pushed contralaterally. Cranial deformities and angiographic pathological changes are constantly found and very pronounced. No clear contrast filling was observed in two out of three cases at early or late cisternograms. How to interpret the Galassi observations-is it certain that they show direct communication Whether the contrast filling of the cyst in the hours after intrathecal injection, as observed by Galassi et al. With this time span, it is conceivable, perhaps even probable, that the cyst was filled by diffusion over the thin cyst membrane of the water-soluble metrizamide rather than by a direct communication. The partial volume effect in a single-slice scanner with thick slices will have the same apparent effect as diffusion in a communication study; namely that smaller cysts might appear (partly) contrastfilled, while larger cysts do not. A study of prenatal ultrasound and postnatal magnetic imaging in the diagnosis of central nervous system abnormalities. Non-neoplastic cystic lesions of the sellar region presentation, diagnosis and management of eight cases and review of the literature. Diffusion tensor imaging in a symptomatic patient with an intra-axial arachnoid cyst. Cine-magnetic resonance imaging evaluation of communication between middle cranial fossa arachnoid cysts and cisterns. Language localization in cases of left temporal lobe arachnoid cyst: evidence against interhemispheric reorganization. Symptomatic arachnoid cyst of the left frontal convexity presenting with memory disturbance-case report. The clinical classification and treatment of middle cranial fossa arachnoid cysts in children. Many colleagues advocate a strategy of repeated neuroimaging procedures to see if the cyst grows. As cyst growth has been demonstrated in only five adults worldwide, this strategy seems to lack any rationality. Judged by the number of publications, cyst disappearance appears to be more common than the postnatal growth, as will be demonstrated in the following. The main finding in the oldest study [2] is that there seems to be a statistically significant correlation between patient age and volume for cysts larger than the volumetric mean, but not so for cysts smaller than the mean. These authors found that cyst enlargement over time took place in 17 children (19. In six patients, the cyst enlargement ceased, and spontaneous volume reduction was observed in three patients. This applies above all to de novo cysts that with certainty have developed after birth; this phenomenon has only been reported in 26 young children, mostly infants, and never in adults. Spontaneous cyst disappearance or resolution has also been described in adults, however, most often in children. Most of these patients were children; 23 patients were 16 years or younger, four of them infants. The majority of the cysts (18) that disappeared were located in the middle fossa (left/right ratio: 10/8), 16 males and two females. Five cysts had a prepontine/suprasellar location, three were overlying the frontal cortex, and two were found in the posterior fossa. There was a marked preponderance of male patients in the survey, 21 males versus 6 females, mainly because of the large number of males in the middle fossa cyst group. The distribution of cyst locations does not seem to deviate much from the distribution one can find in large, population-based patient cohorts [36]. Rather surprisingly, the cyst had then disappeared completely without any known trauma. Consequently, in most cases it is impossible to know whether a cyst developed before or after birth. Exactly when these cysts developed postnatally is not known, but the period during which it happened is reported. The relatively high number of suprasellar cysts in this small survey is surprising, as it does not correspond to the frequency one usually sees in larger patient cohorts [36,39]. This apparent overrepresentation may be incidental, but it may also be caused by a valve mechanism: the excess extracerebral fluid that one often sees in infants gets access to and fills a preformed space via a slit valve; such valves have been demonstrated only for suprasellar cysts, see below and Chapter 8, the "Valve Mechanism". The by far most intriguing publication on postnatal development of new cysts, however, is that of Mattei et al. Nine of the cysts were located on the left side, four were found in the right middle fossa, and as many as five children had bitemporal cysts. The sidedness distribution is within what one can expect from previous population-based studies, but the relatively high proportion of bilateral cysts (27. Pediatric arachnoid cysts and subdural hygromas in early infancy: challenging the direction of the causality paradigm. When this defect in early childhood is exposed to extracerebral fluid under pressure, as. The only problem with this model is that a slit-valve has been demonstrated only in suprasellar cysts [42,43] (see also Chapter 8, the "Valve Mechanism"), not with certainty in any other cyst locations. Moreover, analyses of cyst fluid and genetic studies indicate that middle fossa cysts more likely are filled via fluid transport across the cyst wall rather than via a slit-valve [44,46]. These children were followed-up with neuroimaging and it was found that further growth of the cyst took place in 17 children (19. Five of the patients were 18 years-of-age or above when the cyst enlargement was discovered, the oldest being 81. Four of these nine growing cysts were located in the temporal fossa, four had a suprasellar location and one was located in the posterior fossa.

Critical 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 role for Fas-associated death domain-like interleukin-1-converting enzyme-like inhibitory protein in anoikis resistance and distant tumor formation milk allergy symptoms in 3 year old purchase discount allegra line. Apoptotic signalling during initiation of detachment-induced apoptosis ("anoikis") of primary human intestinal epithelial cells allergy forecast elgin tx discount 120mg allegra fast delivery. Inhibition of caspase-dependent mitochondrial permeability transition protects airway epithelial cells against mustard-induced apoptosis allergy symptoms aches pains purchase allegra cheap online. Oncogenic ras-induced down-regulation of pro-apoptotic protease caspase-2 is required for malignant transformation of intestinal epithelial cells allergy gluten discount allegra 120 mg fast delivery. Integrin 81 confers anoikis susceptibility to human intestinal epithelial crypt cells allergy medicine making me dizzy cheap allegra online master card. Integrin v3 promotes anchorage-dependent apoptosis in human intestinal carcinoma cells allergy shots itchy discount 120mg allegra with amex. Role of integrin v3 in substrate-dependent apoptosis of human intestinal carcinoma cells. Repressed 257 258 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 E-cadherin expression in the lower crypt of human small intestine: a cell marker of functional relevance. Integrins as mediators of epithelial cell-matrix interactions in the human small intestinal mucosa. Regulation of apoptosis during homeostasis and disease in the intestinal epithelium. Apoptosis-programmed cell death and its relevance to gastrointestinal epithelium: survival signal from the matrix. Early establishment of epithelial apoptosis in the developing human small intestine. Human intestinal epithelial cell survival; differentiation state-specific control mechanisms. Early acquisition of bowel segment-specific Bcl-2 expression profiles during the development of the human ileum and colon. Differential sensitivity to apoptosis between the human small and large intestinal mucosae: linkage with segment-specific regulation of Bcl-2 homologs and involvement of signalling pathways. Laminins in the 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 developing and adult human small intestine: relation with the functional absorptive unit. Differentiation state-selective roles of p38 isoforms in human intestinal epithelial cell anoikis. Suppression of anoikis in human intestinal epithelial cells: differentiation state-selective roles of 21, 31, 51, and 64 integrins. Expression of functionally distinct variants of the 4A integrin subunit in relation to the differentiation state in human intestinal cells. Human intestinal epithelial cell survival and anoikis: differentiation state-distinct regulation and roles of protein kinase B/Akt isoforms. Mechanisms of muscle degeneration, regeneration, and repair in the muscular dystrophies. Mechanisms that link the oncogenic epithelialmesenchymal transition to suppression of anoikis. Extracellular matrix: a gatekeeper in the transition from dormancy to metastatic growth. Crosstalk of oncogenic signalling pathways during epithelial- mesenchymal transition. Integrin-linked kinase regulates migration and proliferation of human intestinal cells under a fibronectin-dependent mechanism. Early loss of E-cadherin from cell-cell contacts is involved in the onset of Anoikis in enterocytes. Epidermal growth factor receptor is involved in enterocyte anoikis through the dismantling of E-cadherin-mediated junctions. Met receptor-induced Grb2 or Shc signals both promote transformation of intestinal epithelial cells, albeit they are required for distinct oncogenic functions. The coordinated mode of cell death that generates the components of these skin structures is called cornification. The distinctive features of cornification are extensive crosslinking of cellular proteins and the maintenance of dead cell corpses as functional elements of the Apoptosis and Beyond: the Many Ways Cells Die, First Edition. Cornification differs mechanistically from all other types of cell death and strongly depends on the preceding steps of epidermal cell differentiation, which prepare the cell for its execution [1]. Others include melanocytes, Langerhans cells, and Merkel cells, all of which have specific functions in the interaction of the body with the environment. However, only keratinocytes contribute significantly to the skin barrier against mechanical damages and the uncontroled passage of substances through the body surface. The latter functions depend on the unique ability of keratinocytes to cornify and establish resilient intercellular connections [2]. The epidermis is constantly renewed by the proliferation of cells in the basal layer, by differentiation in suprabasal layers, by cornification of differentiated keratinocytes, and by desquamation of superficial dead cells. The sheet-like structure of the epidermis is interrupted by hair follicles, in which the epidermal epithelium is modified to allow for the continuous growth of hair. The formation of the hair shaft involves a special mode of differentiation, in which keratinocytes establish a highly interconnected cytoskeleton and retain intercellular connections. Both interfollicular and hair keratinocytes undergo cornification, but with distinct differences in its mechanism [3]. In the first case, both daughter cells keep contact with the basement membrane and retain their proliferative potential. If, however, the cell division is oriented vertically relative to the basement membrane, one daughter cell detaches from the membrane and conse quently ceases proliferation. Instead, this cell starts a differentiation process that involves further movement away from the basal layer due to the pressure of newly formed cells. The targets genes of the transcriptional regulators of keratinocyte differentiation code for proteins that ensure the structural integrity of the epidermis and for enzymes that facilitate the remodelling of the cell structure, as well as alterations in cellular metabo lism when cells approach the body surface [6]. These keratins heterodimerize and form filaments, which are connected to neighboring cells via desmosomes and to the basement membrane via hemidesmosomes. Intermediate filaments are also attached to the nuclear membrane via plectin, nesprin-3, and perhaps other yet-uncharacterized linkers [7,8]. When kerati nocytes move to the suprabasal layers, they cease to express K5 and K14 and start the expression of K1, K2, and K10. In the human epidermis, the expression of K1 precedes that of K2, and both appear to interact with K10. By contrast, K1 and K2 are expressed in a mutually exclusive manner in the mouse, where K1 and K10 form the suprabasal cytoskeleton in the interfollicular epidermis of body regions with a dense hair coat, whereas K2 and K10 are the main components of the cytoskeleton in the epidermis of ears and soles [9]. High levels of keratin gene expression increase the keratin content of differentiating keratinocytes to over 80% [10]. In the epidermis, filaggrin (filament aggregating protein) is the best-characterized keratin regulator. Filaggrin belongs to the S100 fused-type protein family and, accordingly, consists of an amino-terminal S100 domain and a long repetitive carboxy-terminal domain. Expression of the filaggrin gene during late differentiation of keratinocytes results in the accumulation of the proform of filaggrin in the form of keratohyalin granules. These structures are the distinctive feature of the granular layer of the epidermis. Proteolytic processing of pro-filaggrin, which depends on prior desphos phorylation, releases mature filaggrin, which contributes to the aggregation and bun dling of keratin filaments [11,12]. Besides interacting with keratins, filaggrin also serves as an important source of urocanic acid, an endogenous sunscreen [13]. The mechanical resilience of the epidermis depends both on keratin filaments within individual cells and on the linkage of neighboring cells via desmosomes. Cornified cells are thus detached from the epidermis and shed to the environment in a process named desquamation [14]. Hair keratinocyte differentiation follows the same basic principles as interfollicular epidermal keratinocyte differentiation. However, 186 Apoptosis and Beyond there are notable differences between epidermal and hair differentiation. Most impor tantly, a peculiar cell fate-determination program establishes concentric circles of keratinocytes, which follow distinct differentiation pathways, with specific sets of keratins and associated proteins being expressed in each concentric layer [15]. As keratinocytes move away from the basement membrane, the circular arrangement of cell identities is maintained and a tubular organization of the hair follicles is achieved. Thus, the hair follicle comprises a central hair shaft surrounded by the inner and the outer root sheaths. The hair shaft is further divided into a medulla, a cortex, and a cuticle, and likewise, the root sheaths have several sublayers. In the present context, it is important to note that the functionality of the hair follicle depends on differential cornification of keratinocytes in the various layers. Keratinocytes of the hair shaft cornify and maintain intercellular connections so that a mechanically resilient hair fiber is formed. The outgrowth of the fiber from the surrounding epithelium depends on the scaffolding function of the inner root sheath. There, keratinocytes cornify and later dissociate from the hair shaft so that an essential tissue gap is formed around the growing hair fiber. The keratinocytes of the outer root sheath do not cornify, but maintain the integrity of the epithelial connection between the hair bulb and the epidermis. The latter is crucial because the hair follicle undergoes extensive remodelling during the growth and regression phases of the hair cycle [16]. Moreover, the attachment of sebaceous glands to the hair follicle adds to the complexity of this mini-organ. For a comprehensive description of cell differentiation in the hair follicle, the reader is referred to an excellent review by Langbein and Schweizer [15]. As the molecular aspects of keratinocyte differentiation remain to be determined for several compartments of the hair follicle, the differentiation and cornification program will be described here only for the cells of the hair shaft. Consequently, the aforementioned intracellular compart ments disappear during the transition of cells to the cornified layer of the epidermis. The granular layer of the epidermis is defined histologically, and actually consists of several layers of cells that display progressive accumulation of keratohyalin granules and lamellar bodies. They are not surrounded by a membrane and, therefore, are to be considered part of the cytosolic fraction of keratinocytes. By contrast, lamellar bodies are vesicles with a single membrane border, containing lipid lamellae and proteins. In fact, many proteins in lamellar bodies are identical to proteins of lysosomes [17]. The secretion process accounts for a significant loss of cellular material, and may therefore contribute to the dying of keratinocytes. Little is known about the steps involved in organelle removal during cornification. In one study, lysosomes of this epidermal layer were found to contain and perhaps degrade mitochondria [19]. These data support a role for macroautophagy: the enclosure and transport of cell organelles to lysosomes for degradation in the stratum granulosum. Accordingly, the expression of the recombinant autophagosome reporter green fluorescence protein light-chain protein 3 in mice has been used to visualize autophagosomes in the outer layers of the epider mis [20]. However, the deletion of essential autophagy proteins does not result in severe disturbances of cornification, but appears to be compatible with the formation of a functional skin barrier [20,21]. Taking this all together, autophagy may contribute to the removal of organelles during terminal differentiation. Deletion of this protein in epidermal keratinocytes of the mouse results in the accumulation of autophagosomes, glycogen granules, and condensed nuclei in immature but dead cells on the skin surface. Because they have a defective skin barrier function, newborn mutant mice dehydrate fast and die perinatally [22]. Yet another hypothesis suggests that lysosomes do not primarily take up intracellular content during cornification but rather disintegrate to release their content (hydrolytic enzymes such as proteases of the cathesin family) into the cytosol. The lysosomal enzymes require an acidic pH for optimal catalytic activity, which appears to be incompatible with a role in the neutral milieu of the cytosol. However, the pH decreases at the skin surface, and it is speculated that the intracellular pH may already drop during cornification. Experimental evidence for or against this hypothesis is not conclusive at present. The activity of lysosomal cysteine proteases increases during terminal 188 Apoptosis and Beyond keratinocyte differentiation [23], and lysosomal proteases contribute to distinct sub processes of cornification [3]. This notion is supported by the epidermal phenotypes of mutations in genes for lysosomal proteases. Likewise, deleterous mutations of cathepsin C lead to hyperkeratosis in human patients [27]. Cystatin M/ E inhibits cathepsin L and V and is essential for normal cornification, suggesting that the lysosomal protease activities must be tightly controled in order to prevent aberrant proteolysis [28]. Importantly, cystatin M/E localizes to the cytosol, perhaps indicating that it inhibits cathepsins that are prematurely released from lysosomes. Besides releasing proteases, lysosomes are also a source of enzymes that degrade nucleic acids. As the breakdown of lysosomes occurs in parallel to the breakdown of the nucleus, an interdependence of these processes is conceivable. Interestingly, autophago lysosomal activities and nuclear breakdown are linked in sebaceous glands, where keratinocytes undergo non-cornifying cell death [21].

In the 2-hour group allergy forecast davis ca allegra 120 mg amex, treated cells poorly stained with cytoplasmic lamellipodia-like extensions can be seen without any inclusions allergy symptoms everyday discount 180mg allegra fast delivery. A few isolated cells with poorly contrasted nuclei and a narrow rim of cytoplasm can be discerned allergy shots under the tongue discount 180mg allegra overnight delivery. It also confirms the observations of the Feulgen staining technique allergy symptoms sneezing runny nose order online allegra, as well as those of densitometry allergy and immunology salary buy cheap allegra 180mg line. Many of these tumor cells undergo changes in normal cultivation that allow them to die of either apoptosis allergy testing for bees best order allegra, some rare form of necrosis/oncosis, or, following prooxidant treatment in our experiments, mainly autoschizis (see Table 28. A few fat-containing vacuoles can be detected by the presence of a residual osmiophilic content. A large number of rough and smooth endoplasmic cisternae are distributed throughout the remaining cytoplasm. The large nuclei appear ovoid, or else are deeply indented by a deep, narrow groove. The overall nucleoplasm is euchromatic, with a delicate thickening of the inner nuclear membrane clearly interrupted by nuclear pores. Unlike in apoptosis, all of these cytoplasmic fragments do not contain detectable membranous organelles or any nuclear fragments (such as apoptotic bodies). As a consequence of these progressive self-excisions, cells diminish in size by more than onethird, leaving organelles clustered around the nuclei in a thin rim of cytoplasm. Top-left image shows a sham tumor cell, with its large nucleus and reticulated nucleolus. In the rest of the images, the nucleus has chromatin redistributed as a peripheral coating of the inner nuclear membrane and extracted from the nucleolus, making a "marbled" patchy thicker outer nucleoplasm that compacts to progressively disappear through chromatolysis. At the same time, the nucleolus compacts as a granular mass with interstices left by retiring chromatin, which become entirely compacted and fragment into smaller size. The treated carcinoma cells decrease in size before chromatolysis with deleterious swelling of the nucleus and bursting of the envelope accompanies autoschizis cell death. The majority of the cells exhibit well-contrasted chromatin, which decorates the inner nuclear envelope in a layer 0. At first, the chromatin remains associated with and penetrates a huge round nucleolus. These become distant from the nucleolar mass and appear only as electron-dense patches along the nuclear envelope. The final stage in the process before karyorrhexis and karyolysis is the swelling of the remaining organelles and nuclear envelope, which disintegrates due to osmotic defects. During these progressive changes, the majority of the mitochondria exhibit condensed bodies in their matrices, while their inner and outer membranes apparently remain intact. The intermediate filaments of the cytoskeleton appear in bundles surrounding the nucleus and the organelles. The cells display ovoid magenta nuclei surrounded by pale-lilac cytoplasm nonspecifically stained by the Schiff base during dehydration of the cells. Cells are superimposed on top of one another, which is indicative of their absence of contact inhibition. However, a small number of cells with large diameters and very large nuclei can also be seen. A time-dependent reduction in the number of adherent cells and of staining contrast for chromatin is also apparent. In this treatment group, the nuclear mass is always detected only with a poorly stained, pinkish chromatic material. The standard-error values are all identical, because they are based on a pooled variance estimate. The diffence in treatment with different cytotoxicities is summarized here for the sake of completion and comparison [185]. Differently sized pieces can be auto- or self-excised by the cell body, which remains as a narrow perikaryal cytoplasmic area. Many pieces of cells or corpses are found in intercellular spaces to confirm these observations. Likewise, there is an increased prevalence of cytoplasmic vacuoles with other organelle damages. Out of this network appears a series of flat, well-contrasted vesicles displaying stiffed-like membranes, revealing apposed, curved, or end-curved rods similar to collapsed Birbeck bodies, each extremity of which displays a small dilated internum. It is flat, appears like stiff cisterns with small dilated luminal extremities that mingle among damaged mitochondria and lysosomal bodies (one markedly so). This patch displays void areas adjacent to an apparently intact fatty droplet (f) and is almost entirely sur rounded by a phagophore-phagosome, sug gesting that glycogen and its cytoplasm are captured. This can be seen in the enlarged area with accumulated lysosomal bodies, which shows their leaky envelopes (open arrowheads). Some mitochondria appear elongated, distorted with thinning aspects, and serpent-shaped. Contiguous or continuous aspects can be found within the lysosomal bodies (curved arrow). The comparative display demonstrates that from a cristolytic morphology (A), the matrix is changed due to swelling and deposition of highly contrasted material, as well as damages. At first, a thin nucleolus and heterochromatin go from a somewhat reduced contrast to clusters of fine chromatic punctate dots, before melting down into a fine to indistinguishable, poorly contrasted, homogeneous aspect, without showing any compaction on nucleoids as in apoptosis or apoptotic bodies. The altered mitochondria demonstrate their electron contrast, and a unique stretched, twisted-like morphology (arrows) near onion (phagosomes) bodies; some dilated intermembranous spaces can be vacuolated. The cytoplasm contains innumerable particles (free ribosomes mixed with b-glycogen) and scattered pieces of endoplasmic cistern. The nucleoplasm shows fine granulation, resulting from heterochromatin dilution and disaggregation. Some cells found in the 1 m-thick sections are nucleated, confirm ing the blockages in the cell cycle described by Jamison and colaborators [176,188]. The accumulated nucleolar masses can be dismantled and fragmented, leaving one mass of condensate ribonucleoproteins further shrinking the nucleoplasm and losing its chromaticity. Note the chromatin leaving the nucleolus (C), and the karyorrhexis and progressive karyolysis producing a clearing of the nucleoplasm, which become flocculent with almost total washout (I). Nucleolar damage encom passes segregation of the cellular components and fragmentation of their ribonucleoprotein masses. In the same cell areas, the altered mitochondria are captured or linked with lysosomes through membranous liners and become constituents of the amassed autophagosomes [113,148]. It is of interest to try to work out (based on ultrastructural observations that show phagophores and autophagocytotic events) which structures produce these endomem branes. These display a typical curly aspect, either by themselves or in continuity with the outer-membrane extensions of the lysosomal bodies; they range between 1. These structures can evolve into phagosomes with increased segregation of altered organelles and segments of cytoplasm, and the vacuoles can eventually link and fuse altogether, contributing to the self-excision of pieces of cell or to autoschizic cell degradation, which involves the shedding of cell pieces or corpses. Numerous and sometime prominent autophagosomes can be seen adjacent to or as an extension of the nuclear envelope. This induced process of tumor-cell demise is the most frequently observed in vitro, and is what is termed "autoschizis cell death" [35]. Among the perikaryal organelles, small mitochondria with minute matrical condensation and variable-sized, electron-dense autophago somes can be seen. Inclusions suggestive of large mitochondria, including a large one adjacent to the nuclear envelope, are also visible (black arrowhead). Mitochondria, in most fields of view, are altered and reveal a small size and dimorphic shape compared with sham-treated cells. The cove-like areas around the nucleus contain congregations of a few intact-like organelles, along with many osmiophilic bodies. They appear as if they have been corralled or amassed in the remainder cytoplasmic area, as if blocked along suggestive lines of damaged microtubules issued from a remaining centrosome [113]. After this treatment, most of the surviving tumor cells will have a high nuclear:cytoplasmic ratio. This activity decreases during the second hour (2 hours) and becomes difficult to appreciate at later time points (4, 8, and 24 hours). Cytoplasmic damage includes continuous small auto- or self-excisions (autoschizis), recognizable by the cellular debris 28 Autoschizis 645 scattered among the remaining cells. These excised pieces confirm the smaller diameter of the examined cells (Table 28. Near the time of cell demise by autoschizis, some mitochondria can still be recognized; these are swollen, and are eventually sur rounded by phagophores, with remnants of cristae still showing. The data presented in this chapter seem to be supported by these critical observations. Other nuclei with marginated chromatin exhibit condensed and enlarged nucleoli (small arrow). The only observation we made was of the dysmorphology and segregation of the nucleoli of tumor cells, with ultimate compaction of ribonucleoproteins after chromatin left the nucleolus, leaving empty interstices. This was followed by compaction, and later fragmentation, of the amassed granular structures among the nucleoplasm. Up to 20 nucleoplasm aggregates of separated chromatic dots create ovoid to circular patches of 0. All these nuclear events are indicators of irreversible cell injuries preceding the demise of the tumor cells by autoschizis. With immunolabeling and other biochemical investigations, specific steps and differences can be further elucidated. Again, in both treatment regimens, most organelles are segregated into a large cytoplasmic sector facing the concave side of the indented nucleus. Densitometry analysis of the staining intensity of control and vitamin-treated tumor cells produced optical density values of 0. The presence of mitotic figures indicates that cells in this tumor were still actively dividing. Although the incidence of mitosis was small, the difference between control and vitamin-treated cells was statistically significant (p < 0. The nuclei of some cells appeared pyknotic, while others showed marginated chromatin and predominant condensed nucleoli. This section was also characterized by the presence of many vacuolated cells and of cell necroses. Note the high nuclear:cytoplasm ratio and the fact that there are some cryptic structures among the tissue, created by the signet cells and cell deaths, which contribute to shrinking the tumor after treatment. The nature and biological mechanisms of these nucleases are often associated with the notion that alkaline types. All sorts of pathologic conditions can alter these enzymes (viral, bacterial, degeneration, autolysis, regeneration, "fasting" in liver, etc. Some proteinaceous components of the lysosomal membranes and latent enzymes of the lysosomes or their membrane attachments depend on the status of sulfhydryl groups [213]. Recent advances in the field suggest mechanisms like these involve nuclease blocks. According to the earliest work using histochemistry [1], a deficiency of nuclease activity was seen in more than 60 different animal and human tumors. The decrease and even disappearance of such activity during experimental liver carcinogenesis has also been reported [244]. This affects cancer cell integrity, through membrane and protein damage to these structures. Because endonuclease activation is one of the earliest changes denoting irreversible commitment to cell death, it is generally believed to be involved in the triggering of cell death, rather than the result of it. This protein complex resides in the nucleus and is activated by caspase-3 cleavage of the inhibitor and its subsequent dissociation from the endonuclease. This corresponds to a significant degradation of the tumors and to survival of the implanted mice [7,9,20,204]. This cytoskeletal disorganization is reflected by blister and bleb formation, as well as by acute distortions in tumor-cell shape [35,51,173,182,183,186]. After 1 hour of vitamin exposure, significant levels of lipid peroxidation and damage to the cell membrane occur, suggesting that wholesale indiscriminate lipid peroxidation is a late event in the cell death process. A number of other cellular processes are also affected by the presence of ascorbic acid, and especially dehydroas corbate, including: modulation of signal transduction, cell-cycle arrest, inhibition of glycolytic respiration, and inhibition of metastasis.

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