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Jeffrey A Brinker, M.D.

Jeffrey A Brinker, M.D.

  • Professor of Medicine
  • Joint Appointment in Radiology and Radiological Science


Adrenergic excitation of cutaneous pain receptors induced by disinhibition in complex regional pain syndrome type I order tranexamic paypal medicine 93 948. Prog Brain Res symptomatic and recovered complex regional pain syndrome in children buy cheap tranexamic 500 mg line medications venlafaxine er 75mg. A new clinical approach for diagnosing reflex sympathetic inflammation and pain sensitization in a rat model of complex regional pain dystrophy generic tranexamic 500 mg mastercard symptoms in spanish. Isoprostanes, novel eicosanoids that sympathetic dystrophy: prospective study of 829 patients. Psychological and behavioral aspects of complex criteria for complex regional pain syndrome and proposed research regional pain syndrome management. A critical review of controlled clinical trials for peripheral randomized, controlled, multicenter dose-response study. Evidence based dose vitamin C on complex regional pain syndrome in extremity trauma guidelines for complex regional pain syndrome type 1. Unlike other tumors, they have the unique ability to involute after proliferation, often leading primary care providers to assume they will resolve without intervention or consequence. As a result, the primary clinician has the task of determining which lesions require early consultation with a specialist. Untreated, the lesion could proliferate, potentially resulting in deprivation amblyopia. Many patients are asymptomatic; however, those with high-fow and/or high-output cardiac failure require pharmacologic therapy with propranolol or corticosteroid. Patil Medical College, Pimpri-Pune, India Abstract: the diagnosis of benign liver lesions have been increased due to current imaging modalities and liver function test. Benign liver lesions include a broad spectrum of pathologies ranging from regenerative nodules to true neoplastic processes and various cystic lesions. Age wise distribution of cases in study group showed that majority of cases were between 21-30 years age group. Amoebic liver abscess is the commonest lesion, which is common in males of 21-40 years. Cavernous hemangioma is the commonest solid lesion with female to male ratio of 2: 1. Introduction Liver isusually associated with malignant tumoursthat could beprimary,or metastatic depositsfrom primary elsewhere in thebody. The other advantageis that infectivelesionsare beingdiagnosed in earlier stagesand are thus amenable to non-invasivemanagement. They may be detected on imagingstudies incidentally, or during investigationof abnormal liver function testsor abdominal pain. Benign hepatic tumoursincludeabroad-spectrum of pathologiesrangingfrom regenerative nodules to trueneoplasticprocesses. Themost common solid benign hepatic tumoursinclude cavernoushaemangioma, focal nodular hyperplasia, hepatic adenomaand nodular regenerative hyperplasia and cystic lesions like Simple liver cyst, pyogenic liver abscess, amoebic liver abscess and hydatid cyst. In themajority of casesof benign hepatic tumours, patientsareasymptomatic andno treatment isindicated initially. The main indication for treatment is thepresence of significant clinical symptomsor suspicion of malignancy or fear of malignant transformation. Thisstudy wasundertaken to evaluate theclinical profile, incidence and epidemiology of benign liver lesionsin thecurrent settingof patient awarenessand widespread availability ofimproveddiagnostic modalities. In our study male were significantly more affected as compared to females (Table 3). Out of total 25 cases of amoebic liver abscess 18 (72%) were male and 7(28%) were female. This is in accordance with study done by Seeto et al, in which 75% cases of amoebic liver abscess were males. Similar findings were observed in study done by Mathur et al, in which common age group was 30 to 50 years. All cases had fever and pain in right hypochondrium, 17 had nausea/vomiting, 21 had loss of appetite and 13 had jaundice. Similar findings were observed in study done by Seeto et al, in which 72% patients had fever and pain in right hypochondrium, 64% had nausea/vomiting and loss of appetite but jaundice was present in only 4% of cases. Similar findings were observed in study done by Seeto et al, Mathur et al and Sharma et al. Similar findings were observed in study done by Lee et al, Rahimian et al and Huang et al in which the mean age was 62. Similar findings were observed in study done by Rahimain et al, Yinnon et al and Wang et al. Among 5 cases of pyogenic liver abscess, the mean total protein and albumin were 5. Among 5 cases of pyogenic liver abscess, 4 were hypoechoic and 1 had mixed echogenicity, 4 had round shape and regular border. This was in contrast to study done by Rahimain et al, in which right lobe involvement was 70. Aspirate culture was Klebsiella pneumoniae in 3 (60%) cases and in 1 (20%) case culture was E. These findings are in accordance to the study done by Gandolh et al and Chamberlain et at.

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Flow cytometry was sufficiently developed that it provided Even with the work of many groups order tranexamic pills in toronto symptoms 7 days after embryo transfer, there is no widely the means for both measuring and separating cells on the basis of accepted stem cell phenotype; in part this may be because expres markers generic tranexamic 500 mg on line medicine 3d printing. They lifetime cheap tranexamic 500 mg visa symptoms intestinal blockage, without affecting its proliferative properties (Nolta and separated from marrow a tiny subpopulation with a defined phe Joran, 2001). To seek earlier stem cells, assays were devel was limited; for example, capacity for spleen colony formation oped in which the end point was permanent reconstitution of both rested on findings from a single animal. Because of these limita lymphoid and myeloid cell populations of heavily irradiated mice. Markers other than those defined strain as the recipient; the other was compatible with the recipient immunologically were proposed. Chaudhary and Ronninson but with a marker, usually a hemoglobin with an electrophoretic (1991) have shown that P-glycoprotein, a cell membrane protein mobility difference. A mixture of the two populations was injected that serves to pump poisons out of cells, was expressed on stem after irradiation; the peripheral blood was then sampled as a func cells. Repopulating cells in the marked population were efflux Hoechst dyes may be a stem cell property (Goodell et al. The design and interpretation of the work required under determine whether cells with capacity for long-term reconstitution standing normal regeneration in each tissue. Muscle stem using separation procedures, have reported a high degree of sepa cells, sometimes called satellite cells, are present between muscle ration of cells detected by the two assays. An example is a sepa fibers; these both proliferate and differentiate to maintain muscle ration experiment using centrifugal elutriation reported by Jones mass. They obtained two fractions, one containing cells that myocardial infarction, the heart heals by fibrosis, rather than by formed colonies in culture or in spleen; this fraction protected muscle regeneration. Brain animals after irradiation, but spleen, marrow, and lymph nodes of does contain a population of glial cells that can divide, giving rise long-term survivors were populated principally with host cells. Such cells are most the long-term survival of irradiated mice receiving their second readily seen in the olfactory bulb, which is commonly used for fraction was achieved by mixing the separated cells of the two their study. A genetic taken from mice 60 days after irradiation contained principally marker, often the Y chromosome or one of its gene products, is cells from the fraction without progenitors. Skeletal muscle regeneration is required to show A combination of methods, such as physical separation and differentiation of marrow cells into muscle; cardiac muscle is pre sorting on the basis of phenotypes associated with long-term pared for engraftment by tying a coronary artery leading to infarc reconstituting ability, regularly gave extensive separation of cells tion. Then, long-term repopulating cells are 10 to a 100-fold less frequent after time, cells of peripheral blood were examined to identify (Harrison et al. For example, obtained by culturing marrow from neural stem cell recipients in when secondary colonies are generated by transplantation of cells methylcellulose with appropriate cytokines (see above). Alternatively, stem cells of different the extensive proliferative capacity required for long-term recon tissues might coexist, explaining the results without requiring a stitution (McCulloch, 1993). Both of archies usually implies a unidirectional differentiation from stem these objectives might be met if highly purified stem cells were cells to their descendants, and that stem cells committed to an available. He saw that the differ months later, peripheral blood was tested; engraftment with ence between rapidly growing cancer cells and resting normal purified stem cells was proportional to the number of such cells stem cells might be the basis of a differential effect of certain in the transplanted innoculum. In a series order to provide a selection pressure in favor of hepatocytes of experiments comparing normal and leukemic cells, he and his derived from the transplant. Nodules of proliferating cells were found in their to propose a classification of chemotherapeutic drugs, based on livers. These observations, of great practical these experiments made contamination a very unlikely explana importance for cancer treatment, could only be made with func tion for the observations. For example, there is evidence that stem cells from great patient variation is seen in the karyotypes of the clones, in various sources have phenotypic characteristics in common. Sat response to treatment and in almost every biological parameter ellite cells from muscle and oval cells from liver have surface tested (Fialkow et al. Several growth patterns were seen, varying from no idea that organ specificity is derived from stromal cells, and that growth to profuse proliferation; many colonies sometimes con functional parenchyma is provided by a common population of tained cells with apparently normal differentiation but often with circulating stem cells (Lagasse et al. He found colonies very similar form colonies in the spleens of genetically identical recipients to the normal, but a marked patient-to-patient variation was seen (Bruce and van der Gass, 1963). In cultures from many patient samples, contain cells that were easily shown to be very similar to the leu colonies were small in number or absent, but profuse proliferation kemic cells from which they were derived. The marked patient-to-patient varia tion in blast stem cells again raised the possibility of a stochastic basis for heterogeneity. However, studies of patients at two sequential relapses showed very similar growth patterns, a finding consistent with a clone intrinsic basis for the frequency of clonogenic blast stem cells (McCulloch et al. It was proposed that the blast population was a lineage, headed by blast-committed self-renewing stem cells that could also give rise to nonproliferative blasts. Furthermore, it was proposed that the blast lineage was derived from leukemic pluripotent stem cells, independently of the committed stem cells that differentiated into normal-appearing myelopoietic lineages. In the model, the pre dominant blast cell population coexisted with minor, but detect able, cells of the granulocytic, megakaryocytic, and lymphoid lineages. This latter conclusion was strengthened by the demon stration that separation of T-lymphocytes from blast cells was necessary for blast colony formation (Minden et al. Col system, in which blasts were cultured in suspension and clonogenic umns show the values obtained at presentation. For stem cells in suspension were considered as self-renewal and could a description, see the text. The discovery and cloning of factors that are required for treated with cytoreductive chemotherapy. When Lan was work colony formation by normal cells in culture provided another ing, cure was rare; after chemotherapy, leukemic clones recov link between the normal and leukemic.

The current and continuing important role of ventilation-perfusion scintigraphy in evaluating patients with suspected pulmonary embolism tranexamic 500mg visa medicine 513. American Urological Association: Five Things Physicians and Patients Should Question [Internet] purchase tranexamic 500 mg with amex medicine jar paul mccartney. Are staging investigations being overused in patients with low and intermediate risk prostate cancer? The population level prevalence and correlates of appropriate and inappropriate imaging to quality tranexamic 500 mg treatment skin cancer stage incident prostate cancer in the medicare population. We work with all professionals in nuclear medicine to ensure that Canadians have access to the highest quality nuclear medicine services. Patients over the age of 65 have an increased risk of drug interactions, adverse drug reactions and falls. Although it can sometimes be appropriate to prescribe new medications, a thorough medication review should be done concurrently. Don?t prescribe vitamin B12 injections to clients with low vitamin B12 levels as frst line 2 therapy. Deficiencies are primarily the result of a lack of intrinsic factor (pernicious anemia). Vitamin B12 absorption can also be affected by the regular use of proton pump inhibitors. There is a large body of evidence supporting the efficacy of oral B12 administration in most cases related to pernicious anemia, malabsorption or malnutrition. Furthermore, using the oral formulation will decrease the need for unnecessary clinic visits for vitamin B12 injection, improve efficiency and decrease costs without compromising patient care. After the initiation of therapy, serum vitamin B12 concentrations should be monitored to assess for efficacy. Given the lack of conclusive evidence, vitamin B12 injections should still be considered for patients with severe neurological involvement, ileectomy and significant malabsorption syndromes. Vitamin D deficiency is common in many populations, particularly in patients at higher latitudes, during winter months and in those with limited sun exposure. Therefore, Canadians have inadequate exposure to sunlight, which puts them at risk for vitamin D deficiency. Over the counter vitamin D supplements and increased summer sun exposure are sufficient interventions for most otherwise healthy patients. Don?t do annual complete physical examinations on asymptomatic adults with no 4 signifcant risk factors. Instead, nurse practitioners should counsel their well, asymptomatic patients regarding the importance of screening and focused health assessments performed according to their risk factors. These visits may include specific physical examination maneuvers and screening tests that should occur at intervals informed by the available evidence such as the Canadian Task Force on Preventive Health Care and provincial cancer care organizations. Following evidence based recommendations, including relevant physical examination and screening test guidelines (pap smears, colorectal cancer screening, etc. There is little evidence to indicate that patient outcomes are improved with screening in these populations. Chest X-rays on asymptomatic patients may also result in false positive reporting, which may cause undue stress. The decision to order a chest X-ray should be considered on careful evaluation of any patient presentation indicative of respiratory disease or illness. Don?t order chest X-rays in patients with acute upper respiratory tract infections. Chest X-rays should be reserved for those patients with clinical suspicion of pneumonia, acute upper airway infection with comorbid conditions and those with symptoms persisting beyond three weeks. Pneumonia presents with at least two of: fever, rigors, new cough with or without sputum production or chronic cough with change in colour of sputum, pleuritic chest pain, shortness of breath and localized crackles. Nurse practitioners should be mindful of the risks associated with cumulative radiation exposure such as that from chest X-rays. Don?t order thyroid function tests as screening for asymptomatic, low risk patients. There is insufficient evidence available indicating that screening for thyroid diseases will have these results. These individuals can shed the bacteria upon return home for several months and close contacts and family members may become colonized with the organism. As a safer alterative, travellers should consider prophylaxis with bismuth salicylate given the good evidence for its use. Clinicians may consider prescribing a three-day supply of antibiotics to carry with patients with clear instructions to only take them for severe diarrhea, given the benefit of reduced symptom duration. Cervical cancer is very rare in women younger than 21 years of age even if they are sexually active. Cervical cancer is very rare in women over 65 years of age who have had normal pap smears at regular recommended screening intervals. Screening pap smears done outside of recommended populations could result in false positive findings and lead to unnecessary follow up and treatment. This could result in stress for the patient and expose them to the risks associated with additional investigations and treatments. Monitor for cervical screening guideline changes based on the most up to date evidence. The working group created a list of suggested recommendations based on existing research, experience and common practice patterns. Interventions to improve the appropriate use of polypharmacy in older people: a Cochrane systematic review. Health outcomes associated with polypharmacy in community-dwelling older adults: a systematic review.

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In a recent the adenocarcinoma purchase 500mg tranexamic fast delivery medicine 360, which comprises 80% of series of 62 pancreatic cancers tranexamic 500mg amex treatment menopause, biliary dilatation pancreatic neoplasms discount 500 mg tranexamic amex medications for ptsd, is a solid tumour, usually occurred in 69%, pancreatic duct dilatation in 37% hypoechoic or of mixed echogenicity, with an and the double duct sign (pancreatic and biliary irregular border (Fig. For this reason it is imperative are benign, and gastrinomas, which are more often that the common duct is carefully traced down to malignant. They are usually hypoechoic, well the head of pancreas to identify the cause of defined and exhibit a mass effect, often with a dis obstruction. They are A thorough search for lymphadenopathy and generally smaller at presentation than adenocarci liver metastases should always be made. Pathology of the pancreas, both benign and Colour Doppler can demonstrate considerable malignant, can affect the adjacent vasculature vascularity within the mass and is also important in by compression, encasement or thrombosis. This is due to a relative lack of fatty dep osition and is often more noticeable in older patients, in whom the pancreas is normally hyper Pancreatic metastases echoic. Its significance lies in not confusing it with Pancreatic metastases may occur from breast, lung a focal pancreatic mass. They well-defined, with no enlargement or mass effect, are relatively uncommon on ultrasound (Fig. Focal pancreatitis Widespread metastatic disease can be demon strated on ultrasound, particularly in the liver, and Inflammation can affect the whole, or just part of there is often considerable epigastric lym the gland. Occasionally, areas of hypoechoic, focal phadenopathy, which can be confused with the acute or chronic pancreatitis are present (see appearances of pancreatic metastases on the scan. These are invariably a diag nostic dilemma, as they are indistinguishable on ultrasound from focal malignant lesions (Fig. The acute inflammation has resolved, the obstruction is relieved and the pancreas now appears hyperechoic with a mildly dilated duct, consistent with chronic pancreatitis. The Because malignant lesions are frequently sur duct may be ruptured, with consequent leakage of rounded by an inflammatory reaction, biopsy is also of questionable help in differentiation of focal benign and malignant lesions. The presence of a cystic mass in the absence of these conditions should raise the suspicion of one of the rarer types of cystic carcinoma, or a pseudo cyst associated with acute pancreatitis. The lack of an adjacent lection, but will not differentiate pancreatic secre reference organ, such as the liver, makes assessment tions from haematoma. In patients with insulin-dependent diabetes melli Colour Doppler should display perfusion tus with end-stage renal disease, simultaneous pan throughout the pancreas and the main vessels may creatic and kidney transplant is a successful be traced to their anastomoses, depending on over treatment which improves the quality of life and lying bowel (Fig. Typically such patients sound is particularly helpful in evaluating rejection, also have severe complications, such as retinopathy and it is difficult to differentiate transplant pancre and vascular disease, which may be stabilized, or atitis from true rejection. The transplanted kidney is placed in the iliac fossa with the pancreas on the contralateral side. The donor kidney is transplanted in as usual, with anastomoses to the recipient iliac artery and vein. The pancreatic secretions are primarily by enteric drainage, as the previous method of blad der drainage was associated with an increased incidence of urologic complications such as urinary tract infection, haematuria or reflux pancreatitis. American Journal of Ultrasound-guided fine needle biopsy of pancreatic Gastroenterology 97: 347?353. International Journal of Pancreatology 20: Imaging of cystic diseases of the pancreas. Williams & Pancreas transplantation: contemporary surgical Wilkins, Baltimore, 735?837. The spleen should therefore be Malignant splenic disease 141 approached from the left lateral aspect: coronal and Lymphoma 141 transverse sections may be obtained with the Metastases 141 patient supine by using an intercostal approach. Leukaemia 142 Gentle respiration is frequently more successful Benign splenic conditions 143 than deep inspiration, as the latter brings the lung Cysts 144 bases downwards and may obscure a small spleen Haemangioma 145 altogether. Abscess 145 Lying the patient decubitus, left side raised, may Calcification 145 also be successful but sometimes has the effect of Haemolytic anaemia 146 causing the gas-filled bowel loops to rise to the left Vascular abnormalities of the spleen 146 flank, once again obscuring the spleen. Lymphatics 148 Ultrasound appearances the normal spleen has a fine, homogeneous tex ture, with smooth margins and a pointed inferior edge. It has similar echogenicity to the liver but may be slightly hypo or hyperechoic in some subjects. Sound attenuation through the spleen is less than that through the liver, requiring the operator to flatten? the time gain compensation controls in order to maintain an even level of echoes throughout the organ. The main splenic artery and vein and their branches may be demonstrated at the splenic hilum (Fig. The spleen provides an excellent acoustic win Rarely, the diaphragmatic surface of the spleen dow to the upper pole of the left kidney, the left may be lobulated, or even completely septated. A splenic the spleen may lie in an ectopic position, in the length of below 12 cm is generally considered nor left flank or pelvis, or posterior to the left kidney. The mal, although this is subject to variation in shape ectopic (or wandering) spleen is situated on a long and the plane of measurement used. Ultrasound spleen, or splenunculus, may be located at the demonstrates the enlarged, hypoechoic organ in splenic hilum. These small, well-defined ectopic the abdomen, with the absence of the spleen in its normal position. Splenomegaly Enlargement of the spleen is a highly non-specific sign associated with numerous conditions, the most common being infection, portal hyperten sion, haematological disorders and neoplastic con ditions (Table 6. As with the liver, measurement of splenic vol ume is usually considered inaccurate due to varia tions in shape, and not reproducible. However, the length of the spleen is an adequate indicator of size for most purposes and provides a useful baseline for monitoring changes in disease status. A Its inferior margin becomes rounded, rather than pointed, and may extend below the left kidney (Fig.

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Bone marrow micrometastases and circulating tumor cells: Current aspects and future perspectives order tranexamic amex medications by mail. Detection and clinical implications of early systemic tumor cell dissemination in breast cancer purchase tranexamic with a visa medications multiple sclerosis. Marker genes for circulating tumour cells predict survival in metastasized breast cancer patients order tranexamic with american express symptoms kidney. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. Carcinoma of the ampulla of Vater: Expression of cancer-associated antigens inversely correlated with prognosis. Carcinoma of the ampulla of Vater: prognostic factors after curative surgery: A series of 45 cases. Surveillance programs for early stage non-seminomatous 435/512 Tumor Markers Medical Clinical Policy Bulletins | Aetna testicular cancer: A practice guideline. Test characteristics of alpha? fetoprotein for detecting hepatocellular carcinoma in patients with hepatitis C. The role of endoscopy in the evaluation and treatment of patients with pancreaticobiliary malignancy. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: Update 2003. A population-based study of tumor gene expression and risk of breast cancer death among lymph node-negative patients. Adjuvant chemotherapy for patients with estrogen receptor-postitive breast cancer. A 3-year prospective study on serum tumor markers used for detecting cholangiocarcinoma in patients with primary sclerosing cholangitis. Thymosin beta-15 predicts for distant failure in patients with clinically localized prostate cancer-results from a pilot study. Microdissection? based allelotyping discriminates de novo tumor from intrahepatic spread in hepatocellular carcinoma. Prediction of biologic aggressiveness in colorectal cancer by p53/K-ras-2 topographic genotyping. Relationship of p53 genotype to second-look recurrence and survival in ovarian epithelial malignancy. Comparative p53 mutational analysis of multiple primary cancers of the upper aerodigestive tract. Pleomorphic (giant and spindle cell) carcinoma is genetically distinct from adenocarcinoma and squamous cell carcinoma by K-ras-2 and p53 analysis. Morphologic, histologic, and molecular similarities between adenocarcinomas arising in the gastric stump and the intact stomach. Sporadic and thorotrast-induced angiosarcomas of the liver manifest frequent and multiple point mutations in K-ras-2. Topographic genotyping of colorectal carcinoma: From a molecular carcinogenesis model to clinical relevance. The origin and molecular characterization of adenoid basal carcinoma of the uterine cervix. Prognostic value of p53 and K? ras-2 topographic genotyping in endometrial carcinoma: A clinicopathologic and molecular comparison. Carcinosarcomas (malignant mixed mullerian tumors) of the female genital tract: Comparative molecular analysis of epithelial and mesenchymal components. Malignant transformation in sinonasal papillomas is closely associated with aberrant p53 expression. Bronchioloalveolar adenocarcinoma of lung: Monoclonal origin for multifocal disease. Relationship of p53 gene alterations with tumor progression and recurrence in olfactory neuroblastoma. Diagnostic and prognostic utility of molecular markers in synchronous bilateral breast carcinoma. Analysis of loss of heterozygosity for tumor-suppressor genes can accurately classify and predict the clinical behavior of mucinous tumors arising from the appendix. Determination of sequential mutation accumulation in pancreas and bile duct brushing cytology. Microdissection? based mutational genotyping of serous borderline tumors of the ovary. Frequency of symptoms of ovarian cancer in women presenting to primary care clinics. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. Role of urinary cathepsin B and L in the detection of bladder urothelial cell carcinoma. Association between standard clinical and pathologic characteristics and the 21-gene recurrence score in breast cancer patients: A population-based study. Sentinel node staging for breast cancer: intraoperative molecular pathology overcomes conventional histologic sampling errors. Use of genesearch breast lymph node assay to detect sentinel node metastases in early stage breast cancer. Intra-operative examination of axillary sentinel lymph nodes in breast carcinoma patients. Implications of the sentinel lymph node procedure for local and systemic adjuvant treatment. Comparative evaluation of an extensive histopathologic examination and a real-time reverse transcription-polymerase chain reaction assay for mammaglobin and cytokeratin 19 on axillary sentinel lymph nodes of breast carcinoma patients. Novel intraoperative molecular test for sentinel lymph node metastases in patients 443/512 Tumor Markers Medical Clinical Policy Bulletins | Aetna with early-stage breast cancer.

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Relationship among physical space purchase tranexamic canada medicine x stanford, network topology purchase genuine tranexamic on line keratin intensive treatment, and proteins that form the regulatory network order cheap tranexamic symptoms mold exposure. Some of the combina phase space: various ways of representing how cells process signals. The middle graph represents a protein interaction network in which each open circle together form the phase space, which has N dimensions, one for represents one protein, with the connecting lines indicating their in each protein. The abstract phase space is visualized in the top graph as obvious that the number of possible combinations of activity states a 3D potential surface? with valleys and pits. Each point on the across the genome, and hence the size of the phase space, is huge. Note that the pits (attractors) corre spond to the stable cell fates illustrated in Fig. For instance, because protein p27 inhibits cdk4 activity (Sherr and Roberts, 1999), all theoretically possible network states in which we have, simulta neously, high levels of p27 and high cdk4 activity would not be With such an interaction map in hand, one would then like to possible, although such states are part of the theoretical phase translate it into a phenotypic landscape that captures the biological space. The central notion for doing so is that the interaction networks extending this two-protein interaction to the entire genomewide are not static maps. Rather, they are dynamic because every pro network, it becomes plausible that the overall dynamics of the tein within that web of interactions exhibits a numerical value that network is highly constrained by the underlying protein?protein indicates its actual expression level or activation status, and these interactions. The profile consisting of such expression phase space until they end in stable? states that represent protein and activity values across all the proteins directly maps into the activity combinations that comply with the rules of their under cellular phenotype. Thus, as the marble on the landscape rolls down a and gradients? pointing toward these stable states are be formed. Thus, the phase appears as an amazingly well-orchestrated process is, in fact, an space is not structureless but is divided into valleys and pits. Because attractors are intrinsically stable, net epigenetic landscape that thus can be interpreted as the phase work simulations show that it typically will be necessary to change space of an underlying regulatory network. Then the structure of the attractor biochemical response that branches out to affect multiple genes landscape? with its ridges, peaks, valleys, and pits essentially and proteins. In fact, already in the 1940s, molecular elements within the network, one attractor may be Delbruck (1949) discussed the possibility that differentiation states switched to another. Such sets of are attractors in a genetic circuit that exhibits multiple stable states genes and proteins appear to overlap, and an individual molecule (?multistability). Similar ideas were later expressed by Monod might be part of various transition-causing sets. With recent insights into the detailed dynamics of cell fate pleiotropy also might help to explain why it is relatively simple to regulation in mammalian cells, a finer picture has emerged: cell find extracellular stimuli that can induce a cell fate switch, but also fate switching, such as among growth, differentiation into distinct why attempts to find downstream factors, such as transcription cellular phenotypes, and commitment to apoptosis, similarly obeys factors that control a switch, have proven much less fruitful. Such master the phase space of a network establishes a link between the switch genes themselves have broad downstream effects, includ observed selective nature of cell fate regulation and the molecular ing activation of multiple proteins and other genes that are network of signal transduction. Viewing cell regulation through required to promote the attractor switch, again a result consistent the optics of the phase space may help to explain a series of fun with the attractor paradigm. Default Fates From the landscape metaphor, it is nation in the narrow perspective of instructive pathways. Intrinsic Robustness If the attractors that emerge stable than those with a small basin. This also provides a natural tiated state occupies a very large basin that covers large regions of explanation for the observation that a cell fate can be achieved the phase space accessible to a given cell type, since many nonspe from many different directions,? triggered by a large set of stimuli. This picture thus provides Boundaries of basin of attraction represent a natural decision a conceptual explanation for the widely held notion that the differ making criterion, akin to watersheds. Differential Barriers to Cell Fate Switching Tran anywhere in the phase space because the typical size of the tran sitions among attractors require a complex, high-dimensional sition-causing set of proteins and genes after a perturbation with signal that consists of changes in the activities of multiple pro a single chemical or growth factor is limited. Moreover, the higher the barrier between two typical? environmental signals that the cell in the tissue can be attractor states, the higher the requirements for signal pleiotropy: exposed to, a given cell state has only a limited number of cell more genes and proteins need to be turned on or off in order to fate alternatives available (?neighboring attractors) among which achieve a transition. However, complete genome reprogramming can switch from growth to differentiation than from a differentiated occur by exposing the nucleus to a new cytoplasm, as during state to growth. This might represent a case in transition is almost unidirectional toward differentiation. In fact, which large, nonphysiological distances in phase space are tra when gene expression profile changes were measured versed to place the network state in an attractor that effectively (Fambrough et al. In more general terms, the ease? and directional behavior obeys relatively simple rules that give rise to selective ity of transitions among the cell fates appear to be governed by regulation of robust cell fates. These rules are the consequence of rules that emerge from the underlying dynamic networks that the natural constraints imposed by the underlying intracellular comprise cellular signal transduction. Some transitions occur with ease and may of this form of regulation based on dynamic networks is that it require only a few changes in protein activities, others require allows the cell to integrate a large variety of microenvironmental simultaneous activation of large sets of genes and proteins, and signals, both carried by specific high-affinity messenger molecules still others require very specific signals or never occur. The feasi and arising from nonspecific physical interactions devoid of bility of any particular cell fate switch depends on the position of molecular specificity. The latter type of cues is crucial for pluripo the attractor states in the phase space and the position of the cell tent cells to tune their cell fate decisions to adapt to their physical at the time of stimulation on the phenotype landscape. It is with environment, such as to assemble complex macroscopic 3D struc this background in mind that the occurrence of spontaneous tures that generate and resist mechanical forces. It will be interesting in the future cell behavior that defy conventional linear pathway models. In to measure the phase space structure to reveal the actual neighbor particular, it unites basic principles of developmental cell biology, hood relationships among these differentiation attractors of vari such as intrinsic programs, extrinsic cues, and probabilistic mecha ous tissues. Contextual Signals to Maintain Differentiated should by no means obviate the need for detailed characterization Phenotype Although much of development and differentiation of the specific molecular features that are distinct for each indi appears to be driven by robust intrinsic processes that do not vidual biological process.


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