Thomas J Smith, M.D.

• The Harry J. Duffey Family Professor of Palliative Medicine
• Professor of Oncology

https://www.hopkinsmedicine.org/profiles/results/directory/profile/8283165/thomas-smith

Discussion points One single clamp loader is needed for assembly of the replication complex erectile dysfunction 26 best vardenafil 20mg. For such an important aspect of life otc erectile dysfunction pills that work buy 10 mg vardenafil, cell division impotence drugs over counter purchase vardenafil 10 mg online, do you think that these subunits and other proteins involved in replication are conserved across the domains of life This discontinuous synthesis results in the generation of fragments on the lagging strand called Okazaki fragments erectile dysfunction diabetes qof discount 10 mg vardenafil with mastercard. As previously discussed in a Key Concept above tobacco causes erectile dysfunction buy genuine vardenafil line, the origin of replication (oriC) is the site of replication initiation erectile dysfunction doctor denver buy vardenafil with visa. Several enzymes localize to the region, most of them involved in the initiation of each new strand. Any erroneous base inserted during replication is recognized by the mismatch repair enzymes. These enzymes recognize the methylated parental strand and use it as a template to remove the incorrect base and insert the correct base on the complementary, new strand. There are different Ter sites for counterclockwise and clockwise movement of the replisome on the circular, bacterial chromosome. The outermost sites likely serve as a backup in case the first Ter sites fail to stop the replication fork from moving forward. Tus binding at the terminus physically blocks helicase from moving forward, thus stalling the replication forks. The Bacterial Cell Cycle e155 Circular chromosomes may become catenated after replication, that is, interlocked, which would prevent the chromosomes from separating into the daughter cells. Similar to eukaryotes, prokaryotic chromosomes can undergo recombination between the two daughter chromosomes while replication is proceeding. An even number of crossing over events is ideal as this leaves two distinct chromosomes. However, if an odd number of crossovers occurs, the two chromosomes can become covalently linked (see textbook. As replication proceeds in both directions around the circular chromosome, eventually the two replication forks meet and the daughter chromosomes separate from each other. Each daughter chromosome remains attached to the interior of the cell membrane, so as each cell elongates, the chromosomes completely separate. One daughter cell is a stalked cell and may begin replication and cell division immediately. The other daughter cell is a swarmer cell and must differentiate into a stalked cell before replication can begin. Additionally, CtrA binds to the origin of replication to silence it in swarmer cells until differentiation has occurred. The regulation of replication in Caulobacter is still largely unknown, although a cascade of two-component regulatory systems seems a likely target. The authors of this associated paper utilize time-lapse fluorescence microscopy to investigate the role each of these proteins plays in replication regulation. The authors used fluorescently-labeled origins of replication and were able to observe, in real-time, the origins of replication for both stalked and swarming cells of Caulobacter. After replication, one origin remained attached at the polar end of the stalked cell, while the second origin of replication (from the other newly synthesized chromosome) moved to the opposite pole. Finally, the daughter swarmer cell must differentiate into a stalked cell before it can initiate replication. The replication cycle of a stalked cell takes about 67 minutes and the replication cycle for a swarmer cell takes about 80 minutes. They did, however, determine that the presence of CtrA in cells that were prohibited from dividing, actually delayed the initiation of replication. The researchers overexpressed DnaA protein in cells and observed the effects on chromosome copy number. The number of chromosome copies per cell significantly increased, indicating a role for DnaA in overinitiation of replication. Overexpression of DnaA was also conducted with fluorescently labeled origins of replication. This suggests that DnaA regulates the initiation of replication independent of CtrA. Replication is silenced in the swarming cell type by the regulatory protein, CtrA, at least until the swarmer differentiates into a stalked cell type and can replicate. Discussion points In Caulobacter, DnaA regulates the initiation of replication and CtrA silences replication in swarmer cells until they differentiate into stalked cells. The authors investigated the effects of overexpression of DnaA protein in Caulobacter. Because of the linear nature of eukaryotic chromosomes, these chromosomes must have special structures to help protect the ends. These are the telomeres, which contain short, tandem repeats of about 6 bases long. Therefore, after each round of replication, the telomeres are shortened by about the length of a primer. As such, multiple origins of replication exist to ensure that the entire chromosome is quickly replicated prior to cell division. Replication initiation in vertebrates is less understood, mostly because Sld2 and Sld3 are not conserved in vertebrates. Another protein, RecQ4, is a homolog of Sld2, but no homolog for Sld3 has been found. Treslin is well conserved in vertebrates but no homolog in budding yeast or other model organisms was found. In addition to replication initiation, what role do you think Treslin might play in checkpoint regulation Both processes are semi-conservative, that is each daughter strand contains one strand from the parent and one newly-synthesized strand. Finally, both eukaryotic and prokaryotic replication complexes use a sliding clamp and clamp-loader complex. In another study, the authors showed that Asf1 interacts with the eukaryotic helicases, which link the histone chaperone to the replication fork. This group also suggests that histones removed during replication are retained near the replication fork by Asf1 complexes until replication is resumed, at which point the histones are recycled. In conclusion, H3K56Ac enhances the interaction with histone posttranslational modification proteins, such as Rtt109, and histone chaperones, including Asf1. After replication, the histones must be reintroduced, along with their posttranslational modifications. Also, what do you think would happen if the histones were reintroduced but never received their appropriate modifications Besides H3, other histone proteins are targeted for posttranslational modifications. The authors examined Gcn5 from Saccharomyces l Eukaryotes control the timing of replication and cell division with a cell cycle. Cell division in eukaryotes is further complicated by the presence of the nucleus, which must be removed prior to the separation of the chromosomes and then reassembled after separation. This is then used to make proteins, the ultimate gene products, by the process of translation, as described in Chapter 13. This allows different genes to be expressed under different conditions and allows the organism to adapt to its surroundings. Regulating gene expression may be extremely complex, especially in higher organisms, and several later chapters (Ch. Here, we limit ourselves to discussing the basic role of regulatory proteins in turning genes on or off. Other names for the antisense strand are the non-coding or template strand; other names for the sense strand are non-template or coding strand. Short Segments of the Chromosome Are Turned into Messages Although a chromosome carries hundreds or thousands of genes, only a fraction of these are in use at any given time. In a typical bacterial cell, about 1000 genes, or about 25% of the total, are expressed under any particular set of growth conditions. Humans have around 22,000 protein coding genes whose expression varies under different conditions and in different tissues. Some genes are required for the fundamental operations of the cell and are therefore expressed under most conditions. In the cells of more complex organisms, which have many more genes than do bacteria, the proportion of genes in use in a particular cell at a particular time is much smaller. Different cells of multicellular organisms express different selections of genes depending on their specialized roles in the organism. To create a functional adult, embryonic genes are often expressed only at certain times and in a highly-orchestrated order. Thus, the control of gene expression is much more complex in more complex organisms, although the basic principles are the same. It was defined originally as a genetic unit by complementation using the cis/trans test. In bacteria, it is common to see several structural genes transcribed under the control of a single promoter. Transcription will first be described in bacteria because it is simpler than in eukaryotes. The principles of transcription are similar in higher organisms, but the details are more complicated, as will be shown below. Transcription begins at the end of the promoter, designated 1, and continues until the end of the gene. However, as long as they are wrong by only up to three or four bases, the sigma subunit will still recognize them. The strength of a promoter depends partly on how closely it matches the ideal consensus sequence. Promoters further away from the consensus sequence will be expressed only weakly (in the absence of other factors-but see below). Both the consensus sequences and the proteins that recognize them will diverge in more distantly related organisms. This is of practical importance when genes from one organism are expressed in another as a result of biotechnological manipulations. The use of "expression vectors" to optimize gene expression during cloning was discussed in more detail in Chapter 7. The subunits from bacteria, archaea, and eukaryotes are compared schematically here. The -subunit is required partly for assembly and partly for recognizing promoters. The - (omega) subunit binds to the -subunit, stabilizes it and aids in its assembly into the core enzyme complex. B) the complementary bases form the stem of the hairpin, with the intervening bases forming the loop. Rho-independent, or "intrinsic," terminators do not need Rho or any other factor to cause termination. The Rho hexamer does not form a closed ring, but instead is split open and resembles a lock washer in structure. Some genes, known as housekeeping or constitutive genes, are switched on all the time; that is, they are expressed constantly. In bacteria, these often have both their 10 and 35 region promoter sequences very close or identical to consensus. Other constitutive promoters are further from consensus and expressed less strongly. Nonetheless, if only relatively low amounts of the gene product are needed, this is acceptable. Genes that are only needed under certain conditions sometimes have poor recognition sequences in the 10 and 35 regions of their promoters. In such cases, the promoter is not recognized by sigma unless another accessory protein is there to help. These accessory proteins are known as gene activator proteins and are different for different genes. Higher organisms have many genes that are expressed differently in different tissues. As a result, eukaryotic genes are often controlled by multiple activator proteins, more specifically known as transcription factors (see below). Long ago, the Greek philosopher Plato pondered the political version of this question: "Who will guard the guardians The cell must respond to some outside influence or must be influenced by other internal processes. The regulation of gene expression will be considered in more detail in Chapters 16 and 17. This chapter will be limited to a discussion of the basic mechanisms needed for a promoter to be functional. Maltose is a sugar made originally from the starch in malt and many other sources. The small molecule, in this case maltose, which causes gene expression, is known as the inducer. The result of this is that the genes intended for using maltose are only induced when this particular sugar is available. The same general principle applies to most nutrients, although the details of the regulation may vary from case to case. Negative Regulation Results from the Action of Repressors Genes may be controlled by positive or negative regulation.

The third nucleotide can often be mutated without changing the amino acid for which it codes erectile dysfunction creams and gels purchase 10mg vardenafil fast delivery. Missense mutations are point mutations where a change in a single nucleotide alters the codon so that one amino acid in a protein is replaced with another amino acid erectile dysfunction treatment fruits discount vardenafil 10mg without prescription. Conservative substitutions occur when the amino acid is replaced with another amino acid that is chemically similar erectile dysfunction weight loss buy genuine vardenafil. Nonconservative substitutions occur when the amino acid is replaced with another amino acid that is chemically dissimilar erectile dysfunction protocol book buy discount vardenafil 10 mg online. In-frame mutations are point mutations where either a deletion or insertion of nucleotides (a multiple of three) alters the codon but does not shift the reading frame erectile dysfunction causes anxiety purchase vardenafil australia. The deletion or insertion of nucleotides (not a multiple of three) results in a frameshift mutation erectile dysfunction medicine name in india purchase vardenafil 20mg online. A skeletal muscle biopsy shows histological signs of fiber size variation, foci of necrosis and regeneration, hyalinization, and deposition of fat and connective tissue. Clinical features include symptoms appear in early childhood with delays in sitting and standing independently; progressive muscle weakness (proximal weakness distal weakness) often with calf hypertrophy; progressive muscle wasting; waddling gait; difficulty in climbing; wheelchair bound by 12 years of age; cardiomyopathy by 18 years of age; death by 30 years of age due to cardiac or respiratory failure. Transposon mutations are mutations where a transposon alters the codon so that a gene is disrupted. Transposable element mutations produce no protein at all because the gene is completely disrupted. Translocation mutations are mutations where a section of a gene is moved from its original location to another location either on the same or different chromosome. Translocation mutations produce either no protein or fusion proteins with a novel function. A couple where one member is a t(14q21q) carrier may have a baby with translocation trisomy 21 (Down syndrome) or recurrent miscarriages. A rapid cytogenetic diagnosis of this leukemia is essential for patient management because these patients are at an extremely high risk for stroke. The resulting derivative chromosome 22 (der22) is referred to as the Philadelphia chromosome. Dynamic mutations are mutations that involve the insertion of a repeat sequence either outside or inside the gene. Above a certain threshold length, the repeat sequence is unstable, causes disease, and is propagated to successive generations in expanding lengths. The exact mechanism by which expansion of the repeat sequences occurs is not known. One of the hallmarks of diseases caused by these mutations is anticipation which means the age of onset is lower and degree of severity is worsened in successive generations. This category of dynamic mutations is characterized by the following clinical conditions. Clinical features include mental retardation (most severe in males), macroorchidism (postpubertal), speech delay, behavioral problems. Fragile X syndrome is the second leading cause of inherited mental retardation (Down syndrome is the number one cause). For loss of function mutations to become clinically relevant, the individual needs to be homozygous recessive. This is because for most genes, an individual can remain clinically normal by producing only 50% of the gene product. This is why individuals with an inborn error of metabolism disease are homozygous recessive (rr). However, for a relatively few genes, an individual cannot remain clinically normal by producing only 50% of the gene product. Consequently, in haploinsufficiency, the 50% reduction in gene product produces a clinically abnormal phenotype. For gain of function mutations to become clinically relevant, the individual needs to be heterozygous. A clinical example of a gain of function mutation involves the Pittsburgh variant as follows: a. Methionine 358 at the reactive center of 1-antitrypsin acts as a "bait" for elastase where elastase is trapped and inactivated. The Pittsburgh variant results in pulmonary emphysema because tissuedestructive elastase is allowed to act in an uncontrolled manner in the lung. In addition, the Pittsburgh variant results in bleeding disorder because the Pittsburgh variant acts a potent inhibitor (gain of function) of the thrombinfibrinogen reaction. First, a gene is a hereditary factor that interacts with the environment to produce a trait. Fourth, a polymorphism is the occurrence of two or more alleles at a specific locus in frequencies greater than can be explained by mutations alone (a polymorphism does not cause a genetic disease). Silent mutations may accumulate in the genome where they are called single nucleotide polymorphisms. In unequal crossover, the cleavage and rejoining of the chromatids occurs at different positions on the maternal chromatid and paternal chromatid. A polymorphism results in the maternal chromatid having an extra repeat sequence (no. During Meiosis I Sister chromatid 1 Sister chromatid 2 Sister chromatid 1 Sister chromatid 2 3. A polymorphism results in one sister maternal chromatid having two repeat sequences (no. Chapter 9 Proto-Oncogenes, Oncogenes, and Tumor-Suppressor Genes I Proto-Oncogenes and Oncogenes A. A proto-oncogene is a normal gene that encodes a protein involved in stimulation of the cell cycle. Because the cell cycle can be regulated at many different points, proto-oncogenes fall into many different classes. An oncogene is a mutated proto-oncogene that encodes for an oncoprotein involved in the hyperstimulation of the cell cycle leading to oncogenesis. This is because the mutations cause an increased activity of the oncoprotein (either a hyperactive oncoprotein or increased amounts of normal protein), not a loss of activity of the oncoprotein. Instead, most human cancers are caused by the alteration of proto-oncogenes so that oncogenes are formed producing an oncoprotein. A single mutant allele is sufficient to change the phenotype of a cell from normal to cancerous. Note: proto-oncogenes only require a mutation in one allele for the cell to become oncogenic, whereas tumor-suppressor genes require a mutation in both alleles for the cell to become oncogenic. A translocation results from breakage and exchange of segments between chromosomes. This may result in the formation of an oncogene (also called a fusion gene or chimeric gene) which encodes for an oncoprotein (also called a fusion protein or chimeric protein). This results in a hyperactive oncoprotein that hyperstimulates the cell cycle leading to oncogenesis. These extra copies are found as either small paired chromatin bodies separated from the chromosomes or as insertions within normal chromosomes. This may result in the formation of an oncogene by placing a gene in a transcriptionally active region. Burkitt lymphoma t(8;14)(q24;q32) is caused by a reciprocal translocation between band q24 on chromosome 8 and band q32 on chromosome 14. This results in increased amounts of normal protein that hyperstimulates the cell cycle leading to oncogenesis. The G protein is attached to the cytoplasmic face of the cell membrane by a lipid called farnesyl isoprenoid. A tumor-suppressor gene is a normal gene that encodes a protein involved in suppression of the cell cycle. Many human cancers are caused by lossof-function mutations of tumor-suppressor genes. Note: tumor-suppressor genes require a mutation in both alleles for a cell to become oncogenic, whereas, proto-oncogenes only require a mutation in one allele for a cell to become oncogenic. These genes encode for proteins that either regulate the transition of cells through the checkpoints ("gates") of the cell cycle or promote apoptosis. Loss-of-function mutations in gatekeeper tumor-suppressor genes lead to oncogenesis. Loss-of-function mutations in caretaker tumor-suppressor genes lead to oncogenesis. How can cancer due to tumor-suppressor genes be autosomal dominant when both copies of the gene must be inactivated for tumor formation to occur The inherited deleterious allele is in fact transmitted in an autosomal dominant manner and most heterozygotes do develop cancer. However, while the predisposition for cancer is inherited in an autosomal dominant manner, changes at the cellular level require the loss of both alleles, which is a recessive mechanism. The bottom photograph of a surgical specimen shows an eye that is almost completely filled a cream-colored intraocular retinoblastoma. The binding of p21 to the Cdk2-cyclin D and Cdk2-cyclin E inhibits their action and causes downstream stoppage at the G1 checkpoint. Clinical features include multiple neural tumors (called neurofibromas that are 4. Note the convoluted, irregular arrangement of the intestinal glands with the basement membrane intact. The bottom photograph shows the colon that contains thousands of adenomatous polyps. Clinical features include early onset of breast cancer, bilateral breast cancer, family history of breast or ovarian cancer consistent with autosomal dominant inheritance, and a family history of male breast. The mammogram shows a malignant mass that has the following characteristics: shape is irregular with many lobulations; margins are irregular or spiculated; density is medium-high; breast architecture may be distorted; and calcifications (not shows) are small, irregular, variable, and found within ducts (called ductal casts). Chapter 10 the Cell Cycle I Mitosis is the process by which a cell with the diploid number of chromosomes, which in humans is 46, passes on the diploid number of chromosomes to daughter cells. The term "diploid" is classically used to refer to a cell containing 46 chromosomes. The term "haploid" is classically used to refer to a cell containing 23 chromosomes. The process ensures that the diploid number of 46 chromosomes is maintained in the cells. The amount of time a cell spends in G0 is variable and depends on how actively a cell is dividing. The G1 phase lasts about 5 hours in a typical mammalian cell with a 16-hour cell cycle. The S phase lasts about 7 hours in a typical mammalian cell with a 16-hour cell cycle. The G2 phase lasts about 3 hours in a typical mammalian cell with a 16-hour cell cycle. Cdk1-cyclin A and Cdk1-cyclin B mediate the G2 S M phase transition at the G2 checkpoint. The M phase is divided into six stages called prophase, prometaphase, metaphase, anaphase, telophase, and cytokinesis. The M phase lasts about 1 hour in a typical mammalian cell with a 16-hour cell cycle. The centrosome complex, which is the microtubule-organizing center, splits into two, and each half begins to move to opposite poles of the cell. The nuclear envelope is disrupted which allows the microtubules access to the chromosomes. The kinetochores (protein complexes) assemble at each centromere on the chromosomes. Certain microtubules of the mitotic spindle bind to the kinetochores and are called kinetochore microtubules. Other microtubules of the mitotic spindle are now called polar microtubules and astral microtubules. The centromeres split, the kinetochores separate, and the chromosomes move to opposite poles. A contractile ring consisting of actin and myosin filaments is found at the cleavage furrow. The two main protein families that control the cell cycle are cyclins and the cyclin-dependent protein kinases (Cdks). A cyclin is a protein that regulates the activity of Cdks and is so named because cyclins undergo a cycle of synthesis and degradation during the cell cycle. The ability of Cdks to phosphorylate target proteins is dependent on the particular cyclin that complex with it. Cdk2-cyclin D and Cdk2-cyclin E mediate the G1 S S phase transition at the G1 checkpoint. A specific recognition protein binds to the amino acid sequence coded by the destruction box that allows ubiquitin (a 76 amino acid protein) to be covalently attached to lysine residues of cyclin by the enzyme ubiquitin ligase. Polyubiquitinated cyclins are rapidly degraded by proteolytic enzyme complexes called a proteosome. Polyubiquitination is a widely occurring process for marking many different types of proteins (cyclins are just a specific example) for rapid degradation. E2F is a transcription factor that causes the expression of gene products that stimulate the cell cycle. A majority of cancers (so-called sporadic cancers) are caused by mutations of these genes in somatic cells that then divide wildly and develop into a cancer. A minority of cancers (so-called hereditary cancers) are predisposed by mutations of these genes in the parental germ cells that are then passed on to their children. In addition, certain cancers are linked to environmental factors as prime etiological importance. From a scientific point of view, the cause of cancer is not entirely a mystery but still remains in the theoretical arena which include the following: A. The standard theory suggests that cancer is the result of cumulative mutations in protooncogenes.

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Has the surgeon made consideration for contingencies in the event of operative failures Has the surgeon become frustrated erectile dysfunction young cure vardenafil 20 mg otc, impatient erectile dysfunction treatment in kuala lumpur 20mg vardenafil, or agitated such that he or she takes excessive operative risks Are anatomic factors at play that could have been mitigated by better planning: large liver boyfriend erectile dysfunction young purchase vardenafil 10mg, short mesentery erectile dysfunction drugs prices cheap vardenafil 10mg overnight delivery, gastric adhesions to the spleen erectile dysfunction protocol does it work vardenafil 10mg, severe bowel adhesions erectile dysfunction treatment delhi purchase vardenafil discount, thick abdominal wall, etc. Other common causes of preventable adverse events involve information flow and planning and staffing. Inadequate information flow involves the poor dissemination of critical clinical data to those who need to act upon them. The nurse does not inform the covering surgeon of significant postoperative tachycardia. The laboratory does not post a substantially lower hemoglobin level until after rounds. Information flow may be related to poor communication, poor training, system problems, or human failures. The key is to create redundant systems and protocols to help reduce human error and decision bias. For example, a covering surgeon is informed that regardless of the clinical scenario, a bariatric patient with a heart rate persistently greater than 120 requires an immediate diagnostic action and plan. A surgeon may feel rushed to complete an operation before scheduled office hours (would not recommend mixing office and operating schedule). The use of checklists is commonplace in aviation, in nuclear energy companies, in construction sites, and in research labs. In fact, in any place where a complex series of events are necessary to ensure a positive and safe outcome, checklists are often present. Surgical checklists have been shown to substantially decrease morbidity and mortality after general surgery. The World Health Organization preoperative surgical checklist reduced major complications from 11 to 7 %. Despite quite striking data, surgeons are still reluctant to implement the systemic use of checklists. Specific Examples of High-Liability Events Anastomotic Leak the most common cause of bariatric surgery litigation is the delay in diagnosis associated with an anastomotic leak. Thus, bariatric surgeons are obligated to develop a system in which anastomotic leaks are recognized and treated rapidly. While the time period that constitutes a "delay in diagnosis" has no clear-cut medical threshold, regardless of the period, a poor patient outcome will result in litigation claiming a delay in diagnosis. Thus, to avoid litigation and to minimize patient harm, if a patient has a reasonable probability of having an anastomotic leak, action must be undertaken. While not all patients with enteral leaks have obvious symptoms-such as persistent tachycardia, progressive abdominal pain, leukocytosis, fever, and dyspnea-consideration of a leak should be made for any patient who is not progressing as expected after gastric bypass. Improving outcomes after bariatric surgery start by developing a team and a system to assist in the diagnosis and rapid treatment of an anastomotic leak. A common delay seen in litigated cases results from the physicians focusing on pulmonary pathology instead of surgical complications. Not all surgeons have the same experience or skill in performing complex laparoscopic anastomoses. While the technical difficulty of a procedure cannot be predicted with certainty, high body mass index (greater ~60), male gender, high waist/hip ratio, and sleep apnea have been associated with more difficult procedures. Implementing office protocols that limit high-risk patients from the onset may impart clarity to patient 42 Liability Reduction, Patient Safety, and Economic Success in Bariatric Surgery 467 selection until the practice is technically comfortable with high-risk patients. A 2-week low-calorie diet (800 kcal/day) has been shown to acutely decrease liver size, which is a common technical limitation intraoperatively in performing gastric surgery [13]. Preoperative planning may also be helpful in patients who may have significant intestinal adhesions. While the extent of adhesive disease cannot be predicted easily, patients with prior trauma, peritonitis, bowel resections or obstructions, and/or large hernias may be technically challenging for some procedures such as a gastric bypass. In those patients, having the flexibility to make an intraoperative decision to undergo a sleeve gastrectomy or adjustable band may decrease the pressure to perform a high-risk anastomosis. Lastly, the surgeon and operating room team have an obligation to cancel a procedure in the event of impairment from sleep deprivation, which is associated with an 83 % increase risk of complications [14]. While not always possible, the surgeon should make every effort to have a consistent operating room team who is aware of specialized instruments, operative techniques, and difficult airway management. Consistent operating room teams who are partners with the surgeon are invaluable to the safety of the patient. Standardization of technique also helps the operating room team follow the procedure with the surgeon and predict when difficulties arise or even point out errors. Intraoperative leak tests certainly do not eliminate the possibility for a postoperative leak; however, when performed with the assistance of an experienced team, the risks of leak tests are minimal. Negligence occurs when obvious signs of a leak are present and there is a delay in treatment, diagnosis, and/or inappropriate treatment. Persistent tachycardia, even in the setting of normal radiographic studies, should never be ignored and usually signifies an anastomotic leak or bleeding. Other causes of tachycardia may be considered only when these surgical complications have been definitively ruled out-if necessary, through operative means. Critical to the management is the training of nurses, residents, and covering physicians of the signs and management of anastomotic leaks and who should have explicit instructions when information should be immediately communicated with the attending. Wernicke-Korsakoff syndrome in a bariatric patient often results in very large cash judgments, as surgeons are responsible for the clinical diagnosis, the early stages are reversible with therapy, and, without treatment, patients are permanently disability. Patient Selection, Consent, and Fraud While the lack of informed consent is rarely the primary cause of patient harm and litigation, the lack of documentation that an informed consent process has taken place may be a mitigating factor. Furthermore, surgeons may feel strong pressure to offer surgery to patients who do not meet the National Institutes of Health criteria for bariatric surgery. Claims of negligence that occur in these individuals are exceptionally difficult to defend. Procedures that are not standard and acceptable treatments for obesity should not be performed outside the purposes of research. Furthermore, a formal credentialing process is strongly recommended when adopting new procedures or technologies (either new to the institution or new to the surgeon). Caution must be used when writing "vital signs stable," especially when they are not! Operative dictations should be completed immediately after surgery and should especially expand on any critical judgments made at the time of surgery. A jury and plaintiff attorney will doubt the truthfulness of an operative dictation performed after a complication is discovered. Meaningful office notes and documentation of important phone conversations are often critical in the defense of a malpractice claim. Patients who are vomiting after bariatric surgery are prone to develop irreversible, debilitating central and peripheral nerve damage due to thiamine (B1) deficiency. This deficiency can occur within weeks of surgery and often presents with spitting, vomiting, depressive, and/or psychotic behaviors, weakness, and Marketing Lastly, there are considerable dangers in marketing bariatric surgery to the public. All marketing materials, such as website content and educational public presentations, are discov- 468 R. Surgical adverse events, risk management, and malpractice outcome: morbidity and mortality review is not enough. Does surgical quality improve in the american college of surgeons national surgical quality improvement program: an evaluation of all participating hospitals. Riskadjusted morbidity in teaching hospitals correlates with reported levels of communication and collaboration on surgical teams but not with scale measures of teamwork climate, safety climate, or working conditions. Impact of the comprehensive unit-based safety program (cusp) on safety culture in a surgical inpatient unit. Patterns of technical error among surgical malpractice claims: an analysis of strategies to prevent injury to surgical patients. Association of surgical care improvement project infection-related process measure compliance with risk-adjusted outcomes: implications for quality measurement. Risks of complications by attending physicians after performing nighttime procedures. Learning about the litigation process and understanding that you can impact the outcome of a potential claim are the key. More importantly, focus on reducing the potential of an adverse event in a serious, consistent fashion. This is more often than not based on uncontrollable and random factors and not malpractice. Open, honest, and compassionate communication with the patient and the family is not only a great risk management tool but also what patients and families deserve. Patient safety and improved outcomes will continue to take a greater importance, and the authors encourage the readers to embrace this concept. Saxton is the chair of the Health Care Litigation and Risk Management Group and cochair of the Health Care Department at Stevens & Lee. Explain the various bariatric procedures, including revisional surgery, that can be performed via surgical robot. Introduction Robots in general and in the medical arena have always been the source of great awe. For example, in the movie the Empire Strikes Back (1980), medical robots treat Luke Skywalker for trauma, severe hypothermia, and even the loss of his hand. Surgical teams may use medical robots to ream out a premeasured femur for a new hip implant, take a biopsy from K. These relatively "simple" tools have come a long way since their beginnings and developed into very complex technical solutions for certain fields of surgery, such as laparoscopy. An originally independent innovation came from the development of the Data Glove, a wired glove that enabled interaction with virtual scenes. This new technology was put to use in a number of different fields, with varying levels of success. Gaming giant Nintendo utilized the design in the Power Glove, a video game controller that ultimately flopped. However, the Data Glove technology appeared very promising in robotic surgery, opening up new possibilities in the field. Telesurgery could ameliorate this issue by allowing doctors to conduct remote trauma surgery on seriously wounded soldiers who were still on the battlefield or en route to a field hospital. This eliminated the need for surgical staff to hold the camera in place during the procedure. It also allowed for a steadier view and more precise and consistent movements of the camera. It was designed to handle minimally invasive procedures, such as beating heart and coronary artery bypass grafting, as well as complex cardiac procedures, such as mitral valve repairs. Additionally, the da Vinci Si features Fluorescence Imaging, a robotic simulator, and a Dual Console Mode, which allows two surgeons to share control of the manipulators. This lets all four manipulators be controlled simultaneously during complex operations. The da Vinci Surgical Systems are built following an anthropomorphic principle: the motion capabilities of the system are designed to mimic those of its human operator. The original da Vinci Surgical System, the da Vinci S, and the da Vinci Si all consist of three major components: the Surgical Console, the Patient Cart, and the Vision Cart. Robotics for Bariatric Surgery Bariatric surgery is rapidly evolving in the field of surgery as the prevalence of obesity continues to rise in epidemic proportion throughout the world. Surgery currently represents the most successful long-term treatment of obesity and its associated comorbidities. However, operating on obese patients presents a particular challenge due to the physical hurdles caused by the excess body mass. While bariatric procedures were originally performed via open surgery, minimally invasive techniques have largely replaced the open approach, and the advantages of a minimally invasive approach have been well validated with reduced postoperative pain, shorter hospital stay, and lower postoperative mortality [1, 2]. Despite its general feasibility, there are a number of technical limitations associated with performing laparoscopic surgery on obese patients, including limited motion of laparoscopic instruments due to a thick abdominal wall, hepatomegaly, and increased amounts of intra-abdominal fat with limited workspace; reduced surgical dexterity; and poorer ergonomics placing significant musculoskeletal stress upon the surgeon. Several publications from the field of gynecology have described clinical benefits of robotic surgery when operating on obese patients [3, 4]. Interestingly, the first robotic procedure was a bariatric procedure, a robotic placement of an adjustable gastric band, performed by Dr. Jacques Himpens (Belgium) in 1998 [5] using an early version of the da Vinci system prior to its actual market launch. Since then, all of the commonly performed bariatric surgical procedures including Roux-en-Y the Da Vinci Surgical System the da Vinci System is the culmination of a long developmental process that has its roots in the 1980s-era as described previously. Several of these early prototypes showed promise, so in 1995, Intuitive Surgical International was founded to license and develop this technology for civilian use. The researchers aimed to create a system that would be minimally invasive to patients while still giving surgeons the comprehensive viewpoint of open surgery. In December of 1998, the first commercial version of the da Vinci Surgical System platform was delivered to the Leipzig University heart center in Germany. Refinement of the original da Vinci design continued with the addition of a fourth manipulator arm and expansion of the instrument families. These changes were fully integrated into the simplified and streamlined da Vinci S model (released in 2006). The latest product iteration, the da Vinci Si, was released in 2009 and features improved ergonomics, 43 Robotics in Bariatric Surgery 471. Since then, a variety of techniques have been described in a number of publications ranging from a hybrid approach to a totally robotic setup [6, 7]. The fellow was a novice to both techniques, and thus the results represented the learning curve for both techniques. Unfortunately, the work by Sanchez and associates remains the only level one study in the field of robotic bariatric surgery.

The cell can incorporate pre-made fatty acids into its lipids and can also break them down for energy impotence hypnosis order vardenafil 20mg. Fatty acids are taken up as coenzyme A derivatives erectile dysfunction medications that cause generic vardenafil 10 mg overnight delivery, not free fatty acids; hence valsartan causes erectile dysfunction purchase vardenafil without a prescription, the signal molecule recognized by FadR is a longchain acyl-CoA erectile dysfunction medication names buy cheap vardenafil online. In the absence of acyl-CoA erectile dysfunction age 30 purchase vardenafil 10 mg with mastercard, FadR represses the operons for fatty acid degradation and also activates fabA how young can erectile dysfunction start vardenafil 10 mg visa, a gene involved in fatty acid biosynthesis. Fatty acid degradation is induced and in addition the level of expression Current opinion in structural biology of fabA decreases, so fewer fatty acids are manufactured. Nature of the Signal Molecule the substrate specificity and the inducer specificity of an operon need not be identical. One is determined by which molecules fit the active site(s) of the enzyme(s) of the pathway and the other by which molecules fit the binding site on the regulatory protein. Lactose itself is only an apparent inducer, as it does not bind directly to LacI and must first be converted to allo-lactose. For induction of the lac operon by lactose, low levels of both LacY (transport protein) and LacZ (-galactosidase) proteins are necessary. A small amount of lactose must be transported into the cell and be converted by -galactosidase to allo-lactose before it can bind to LacI and induce. The maltose system allows transport and metabolism of maltose and longer oligosaccharides also made of glucose subunits. The maltose system is under positive control and the MalT activator protein actually binds maltotriose, a trisaccharide consisting of three glucose residues. Some repressors are only active when they bind a small signal molecule called a co-repressor. If an amino acid, such as arginine, is present in the culture medium, then the cell does not need to make it. On the other hand, if the amino acid is not present in sufficient amounts, the pathway for synthesis needs to be turned on. In general, the cell should turn biosynthetic pathways off when their products are present in the medium or have been synthesized in sufficient amounts. Occasionally, repressors or activators bind other proteins, rather than small metabolites. For example, Mlc is a repressor that regulates glucose transport and a variety of other genes involved in the uptake and metabolism of monosaccharides. When glucose is absent, phosphate groups accumulate on the glucose transporter or PtsG protein. When glucose enters the cell, phosphate transfers from PtsG to glucose, thus converting it to glucose-6-phosphate. Most PtsG protein is therefore non-phosphorylated when there is plenty of glucose. Unphosphorylated PtsG binds to Mlc, which sequesters the transcription factor at the cell membrane. This form of Mlc cannot repress genes; therefore, the presence of glucose indirectly induces expression of genes involved in glucose uptake and metabolism. Activators and Repressors May Be Covalently Modified Some regulatory proteins do not bind a separate independent signal molecule. Most often this is done by the attachment of a chemical group, usually phosphate (see below). Less commonly, the regulatory protein is altered chemically in some other way, for example, by oxidation or reduction. Examples of bacterial regulatory proteins that are altered by oxidation or reduction are the activators OxyR and Fnr. OxyR is converted to its active form by hydrogen peroxide or related oxidizing agents that oxidize sulfhydryl groups to disulfides. It then activates a set of genes involved in protecting bacterial cells against oxidative damage. When sufficient arginine is present, the arginine acts as a co-repressor by binding to ArgR. B) Glucose enters the cell and is converted into glucose-6-phosphate so removing the phosphate. If the supply of glucose runs out, PtsG will be able to retain its phosphate and Mlc is released. In this case, an Fe4S4 iron sulfur cluster in the N-terminal domain of Fnr is reduced under anaerobic conditions. The Fnr activator then activates genes involved in anaerobic respiration, such as those for nitrate reductase, fumarate reductase, and formate dehydrogenase. One large class of regulatory systems that use a phosphate group is the twocomponent regulatory systems. Although often regarded as characteristic of bacteria, they have also been found in lower eukaryotes, including yeast and slime molds. As the name implies, two-component regulatory systems consist of two proteins that cooperate to regulate gene expression. The second is a sensor kinase that senses a change in the environment and changes shape. Usually the sensor kinase is a trans-membrane protein that senses either physical conditions of some sort. Outside the cell, the sensor domain of the kinase detects an environmental change, which leads to phosphorylation of the transmitter domain. Under anaerobic conditions, ArcB phosphorylates itself and then phosphorylates ArcA. The ArcA~P regulator then represses about 20 genes that are only required for aerobic metabolism and activates half a dozen genes needed when oxygen is absent or very low. In Mycobacterium tuberculosis, the causative agent of tuberculosis, some virulence factors are controlled by two-component regulators. The mother cell keeps a stalk that sticks to the soil or solid surfaces in fresh or sea water. After cell division, her daughter cell, called a swarmer cell, forms a flagellum and swims away to a new location where the cell then reattaches to the surface and converts into a stalked cell. The steps from swarmer cell to stalked cell are highly regulated in step with the cell cycle. Next, the stalked cell divides into two during M-phase, forming another swarming daughter cell that stays in G1 until it attaches to a surface. Phosphorylated CtrA (CtrA~P) is abundant in G1 swarmer cells, and silences the origin of replication, perhaps by precluding the binding of DnaA protein. During S-phase, the gene for CtrA (ctrA) is transcribed and translated into more protein that is phosphorylated. At this point of the cell cycle, CtrA~P acts as an activator protein that induces transcription of genes used in G2 and M phase. Interestingly, CtrA~P does not activate these genes during G1; therefore, some other factor controls whether or not CtrA~P acts as a transcription activator. In this paper, the authors identified a possible candidate that determines whether or not CtrA~P can promote transcription. The paper provides evidence that this protein prevents CtrA~P from activating gene transcription during G1-phase. SciP is only found during G1-phase, and if SciP is depleted during G1, then CtrA activated genes that are normally repressed during G1 become activated. In G1, SciP is abundant, and binds to CtrA~P at the promoter of CtrA-regulated genes. In this state, any newly synthesized CtrA~P is free to bind to the origin of replication, thus preventing replication. As cells enter S-phase, CtrA is dephosphorylated and degraded so that the repressor complex of SciP and CtrA~P are removed from the promoters. After this time, more CtrA protein is made and phosphorylated, but there is no SciP present during these stages of the cell cycle. This moves the cell from S into G2 and converts the newly made daughter cell into a swarmer. These two regulatory events combine to prevent transcription of CtrA-activated genes and CtrA-repressed genes. At the midpoint of S-phase, CtrA is remade and phosphorylated as earlier, but the absence of SciP allows CtrA to act as an activator protein, and CtrA-activated genes are turned on. The direction of movement of the phosphate group along the ArcB sensor protein is shown. This sensor kinase autophosphorylates when it senses that it is inside the host organism. Two-component systems are also involved in those rare cases where bacteria show differentiation between different types of cell (see Focus on Relevant Research on the previous page). Phosphorelay Systems the pathway of phosphate transfer in two-component regulatory systems actually involves four protein domains. These domains are highly conserved among different regulatory proteins and are of two types, those where the phosphate is attached to a histidine residue and those where it is carried by an aspartate. In addition to the two-component regulatory systems, other control systems use phosphorelays. The number of proteins, the total number of phosphate-binding domains, and their arrangement varies in different regulatory systems. For example, the widespread Rcs system has five main proteins (see Focus on Relevant Research on the following page). In eukaryotic cells, especially in multicellular organisms, there are many highly complex signal transmission pathways, which often include one or more phosphorelays. Two-component regulatory systems and phosphorelays are also found in cyanobacteria, a category of algae that use photosynthesis to generate energy. Cyanobacteria are found in every niche on the Earth and have been around for eons. In fact, plant chloroplasts are believed to be degenerate cyanobacteria that became symbiotic within the eukaryotic host cells. During evolution, the photosynthetic genes were maintained and the remaining genes for independent growth were lost. The bacteria use antennae called phycobilisomes to absorb the available light from the environment. The genes are controlled by a sensor histidine kinase, RcaE, which has a light sensing pigment on its extracellular surface. Light activation of RcaE triggers autophosphorylation, and then the phosphate group is transferred to RcaF. The discovery of two-component systems in cyanobacteria suggests that this type of gene regulation has been used throughout evolution. However, it is involved in a wide range of other phenomena including cell division, motility, biofilm formation, and virulence. The Rcs system is widely distributed among the gram-negative bacteria including enteric bacteria such as E. The Rcs phosphorelay system has five components: RcsF, RcsC, RcsD, RcsB, and RcsA. The sensor, RcsF, is an outer membrane lipoprotein that triggers the cascade by autophosphorylation. The authors have identified a new domain on the RcsD protein that interacts with RcsB. Specific versus Global Control Many bacteria can grow on a wide range of sugars, such as fructose (fruit sugar), lactose (milk sugar), and maltose (from starch breakdown), as well as glucose. When a preferred sugar, such as glucose, is present, less favored sugars, such as fructose, lactose, or maltose, are not used. In molecular terms, this means the genes for using these other sugars are switched off when glucose is available. A regulon is a group of several genes or operons that are turned on or off in response to the same signal by the same regulatory protein. The members of a regulon have separate promoters and are widely separated on the chromosome. The arginine regulon consists of a dozen genes for biosynthesis and transport scattered over nine locations on the chromosome. They are controlled by a repressor, ArgR, which binds arginine as co-repressor, and is unlinked to any of the genes it controls. As noted above, specific regulation refers to control by a signal specific for a small group of genes. Thus, allo-lactose induces the lac operon, maltotriose induces the mal regulon, etc. In contrast, global regulators control large numbers of genes in response to a more general signal or stimulus. Similarly, the maltose genes are regulated by the specific activator protein MalT and also by Crp. Thus, Crp responds to overall carbon source availability and mediates the choice among different sugars. Crp Protein Is an Example of a Global Control Protein Crp is a global activator protein that is required for switching on the genes for using maltose, lactose, and other nutrients less favored than glucose. Only when this has occurred can the genes for using less favored nutrients be switched on. Whether or not the lac operon is switched on or off thus depends on the two regulator proteins, LacI and Crp. Because it is derived from a nucleic acid precursor, it is known as a regulatory nucleotide.