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Case Study Microvessel Density in Non Small Cell Lung Cancer

The Prognosis in Lung Cancer (PILC) project was setup as an international cooperative group aiming to clarify the area of prognostic factors in lung cancer. In the first instance, it was decided to examine microvessel density counts (MVD) (a measure of angiogenesis) as a potential prognostic factor in non-small cell lung cancer (NSCLC) see Trivella et al. (2006). A pilot study was first carried out to identify published studies. Online searches of Medline and CancerLit databases and a trawl of the references included in identified publications initially revealed 23 eligible studies investigating MVD as a prognostic factor in NSCLC. The key words used for the search were lung cancer, lung carcinomas, angiogenesis, neovascularisation, and microvessel. The few previous IPD studies of prognostic factors seem to have begun with a collaborative network already in place see Look et al. (2002). For PILC, however, there was no existing group. We believed that relatively few groups worldwide...

Cigarette Smoking And The Risk Of Stroke

Heavy smoking (> 20 cigarettes day) increases both the incidence 37-41 and mortality from stroke 40,41 , Cigarette smoking is a major modifiable risk factor for subarachnoid hemorrhage 42-48 , In contrast, evidence concerning the role of tobacco in the risk of intracerebral hemorrhage is still controversial, yet it appears that heavy, but not light-to-moderate cigarette smoking, increases the risk 9,38,49,50 , Smoking is dose-dependantly associated with the risk of ischemic stroke 38,46 , Cessation of smoking reduces stroke risk 37,39 , with major reduction within 2-5 years after cessation 37,39,46 , indicating that part of the effects of smoking is reversible. The risk of stroke seems to return to the level of never-smokers in light smokers, but heavy smokers seem to retain an increased risk even though also they benefit from cessation 37 , There are several mechanisms by which smoking may cause stroke. Cigarette smoking causes an immediate, yet reversible increases in blood...

Cigarette Smoking And Cardiovascular Disease

Cigarette smoking-related cardiovascular diseases have been described widely. However, the mechanisms of their effects on cardiovascular system were not totally clear. The effects of nicotine and carbon monoxide on blood vessel walls, unfavorable lipid profiles, increased myocardial work and the decreased oxygen carrying capacity of the blood of smokers contribute to the overall effect of cigarette smoking on cardiovascular disease 3J. Of the increased cardiovascular risk caused by smoking, it is estimated that approximately one-tenth of this is due to smoking-induced changes in serum lipid 4 , The majority of studies indicate elevations in serum cholesterol, phospholipids, triglycerides, low-density lipoprotein (LDL) and increased hepatic lipase activity in smokers, with decreased serum high-density lipoprotein (HDL) cholesterol 5 , A mechanism to explain the link between smoking and some of the observed changes in serum lipid and lipoprotein concentrations includes the...

Smoking and Lung Cancer

Copd Lung Cancer Photos

Lung cancer (fig. 22.26) accounts for more deaths than any other form of cancer. The most important cause of lung cancer is cigarette smoking, distantly followed by air pollution. Cigarette smoke contains at least 15 carcinogenic compounds. Lung cancer commonly follows or accompanies COPD. There are three forms of lung cancer, the most common of which is squamous-cell carcinoma. This form begins with the multiplication of basal cells of the bronchial epithelium and transformation of the ciliated pseudostratified columnar epithelium into the stratified squamous type. As the dividing epithelial cells invade the underlying tissues of the bronchial wall, the bronchus develops bleeding lesions. Dense swirled masses of keratin appear in the lung parenchyma and replace functional respiratory tissue. A second form of lung cancer, nearly as common, is adenocarcinoma,24 which originates in Over 90 of lung tumors originate in the mucous membranes of the large bronchi. As a tumor invades the...

Animal Models of Lung Cancer

Human Lung Cancer Lung cancer is the leading cause of cancer-associated mortality in both men and women. Although susceptibility to environmental carcinogens may be predetermined and follow a pattern of autosomal dominant Mendelian inheritance 2, 3 , lung cancer results from an accumulation of acquired genetic mutations 4-6 . In fact, it is suggested that 10-20 genetic mutations may be necessary for the development of lung cancer 7 , although the discrete steps for the progression of a hyperplastic bronchial lesion to metaplasia and anaplasia have not been uncovered. Tobacco use is the strongest epidemiologic risk for the development of lung cancer and it is anticipated that approximately 10 of all smokers will develop lung cancer over their lifetime 8 . Current paradigms predict that lung cancer results from the widespread exposure of the carcinogen, leading to a process of field cancerization, whereby the entire aerodigestive track is exposed to the offending agents and leads to...

Smoking Cessation

The best way to stop cigarette smoking is never to start. Of current smokers two-thirds will want to quit, three-fourths will have tried to quit and one-third will try to quit every year (Sutherland, 2003). Smoking cessation methods have limited success and the majority of patients who smoke will continue to do so even after pharmacologic and behavior therapy. Even the best methods of combined pharma-cologic and intensive behavioral therapy leads to a quit rate of only 15 at 1 year. This has led some clinicians, possibly out of frustration or because of fears of straining the doctor-patient relationship, to not make smoking cessation a priority with their patients and, in some cases, to not even discuss tobacco as a threat to their patient's health. If we as clinicians do not raise this issue we miss an important opportunity. We run the risk of our patients getting the message from us that cigarettes are not an important threat to their health. We underestimate our impact on...

Assessing Alcohol and Substance Abuse in the Elderly

Second, and perhaps most helpful, are in-home assessments. In addition to standard consumption interviews and listing the prescriptions and home remedies that the elderly use, other data and relatively unobtrusive observations can be employed. These include a history of falls, grooming, odors present in the house (also, obviously, useful for an assessment of tobacco use), bruises at the level of furniture, tremors, incontinence, and many others (many of which could be associated with non-alcohol-related dementias or depression). Naturally, such an assessment would require considerable training and would obviously be available only for that minority of the elderly who receive home care from outside agencies.

Systematic Review of Multiple Studies of Prognosis The Feasibility of Obtaining Individual Patient Data

We consider the advantages of IPD for reviews of prognostic variables and describe in detail a systematic review of microvessel density counts as a prognostic variable for patients with non-small cell lung cancer. We show that such a study is feasible, but note that it may not be cost-effective to attempt to obtain all relevant data.

Behavioral Medicine

Chronic diseases have replaced acute, infectious diseases as the leading causes of death. Those chronic diseases often have cause effect behavioral relationships with unhealthy behavioral habits such as cigarette smoking, lack of exercise, poor eating habits, substance abuse, and so on. Those facts are the main reasons behavioral medicine is one of the most clinically valuable, recent byproducts of comprehensive behavior therapy. Behavioral medicine has already demonstrated great clinical value in preventing and treating health problems. For example, in recent decades there has been a significant decrease in the death rate for cardiovascular diseases. That decrease resulted largely from people making healthy changes in their personal habits and learning healthier techniques of emotional distress management. See Behavioral Medicine.

Distribution in Tumors

The variations in tumor oxygenation during a very accelerated radiotherapy for advanced head and neck carcinoma have been studied in 14 patients at IGR. All the patients (12 men and 2 women) had T3-T4, N0-N2c, M0 tumors of the oropharynx and or oral cavity, and were previous smokers. The accelerated radiotherapy delivered 70 gy in 3.5 wk on primary tumor and clinically involved nodes (62). A median number of

Adaptation to Cancer

According to the American Cancer Society (ACS), cancer is an umbrella term for a group of diseases characterized by uncontrolled growth and spread of abnormal cells.'' Not counting some highly prevalent, rarely fatal forms of skin cancer, the most common cancers are (in order of prevalence) prostate, lung, colon rectal, and bladder (for men) and breast, colon rectal, lung, and uterus (for women). For both men and women, lung cancer causes the most deaths. Although it kills far fewer people than CVD, cancer is perceived as more dangerous, destructive, and deadly. In reality, the survival rate for cancer has been climbing steadily throughout this century. Taking a normal life expectancy into consideration, the ACS estimates that 50 of all people diagnosed with cancer will live at least 5 years. Nevertheless, cancer remains the second-leading cause of death and is associated with significant pain and disability. Another example of behavioral medicine...

Risk Factors For Psp And

The epidemiology of PD has been greatly aided by two natural experiments that generated important hypotheses regarding its etiology. The first was the encephalitis lethargica epidemic, which suggested a role for an infective agent (20). The second was the strange occurrence of MPTP-induced parkinsonism (21), which suggested the role of a neurotoxic agent and led to studies examining the role of pesticides because of its similarity with paraquat (22). The relevance of these models for the etiology of PSP and or MSA is far more questionable. However, in the absence of any other clues, most researchers have simply used risk factors that have been suggested to be important for PD, e.g., smoking behavior, head injury, pesticides, well water, etc., and tested them out in PSP and MSA as essentially a hypothesis-generating exercise.

Behavioral Epidemiology

There were approximately 2,269,000 deaths in the United States in 1993 (latest CDC report). Deaths are accounted for according to major and underlying cause. The traditional biomedical model has emphasized disease-specific causes of death, and pathways to prevention have typically considered risk factors for particular diseases. For example, cigarette smoking is associated with deaths from cancer of the lung. Thus, efforts to reduce lung cancer concentrate on smoking cessation. However, most of the major causes of death are associated with a variety of different risk factors. Furthermore, many risk factors are associated with death from a variety of different causes. For example, tobacco use causes not only lung cancer, but a wide variety of other cancers, as well as heart disease, stroke, and birth complications. Major nongenetic contributors to mortality were examined in an important analysis in 1993 by McGin-nis and Foege. They identified several behaviors that account for large...

Prevention Sciences

Partners for Prevention, a nonprofit organization, emphasizes that there are at least three different components of prevention. These include clinical preventive services, community-based preventive services, and social policies for prevention. Clinical preventive services typically involve medical treatments such as immunization and screening tests. Clinical services may also include counseling and behavioral interventions. Community-based preventive services include public programs to ensure safe air, water, or food supplies, as well as behavioral interventions to change local patterns of diet, exercise, or smoking. Social policies for prevention might involve regulation of environmental exposures or exposure to hazardous materials at the work place. These social approaches also include taxes on alcohol and cigarettes and physical changes to ensure better traffic safety. Examples of these three types of prevention programs are given in Table IV.

Cells and cell culture

Human-human hybridoma HB4C5 cells producing lung cancer specific monoclonal IgM were used for the assay of the Ig production stimulating activity. HB4C5 cell line was a fusion product of a human B lymphocyte from lung cancer patient and a human fusion partner, NAT-30 cells. HB4C5 cells were cultured in ERDF medium (Kyokuto Pharmaceutical, Tokyo, Japan) supplemented with 10 g ml of insulin, 20 g ml of transferrin, 20 M ethanolamine, and 25 nM selenite (ITES-ERDF) at 37 C under humidified 5 CO2-95 air (Murakami et al., 1982).

Results And Discussion

Preliminary analysis of the database (Tables 1 and 2) collected during 15 years (three 5-year intervals) of 844 lung cancer cases suggests a permanent increase of lung cancer incidence in both the most polluted part of the district and the rest of it. The incidence of lung cancer is markedly influenced by exposure to arsenic in occupational settings as can been seen from Table 3.

Potential Biomarkers for Antiangiogenic Therapy

Biomarkers of efficacy of antiangiogenic therapy need to be established to validate these mechanistic hypotheses, to identify responsive patients and optimal doses, and to predict efficacy of regimens that include AAs. Optimizing the dose and schedule of bevacizumab for colorectal, breast, and lung cancer, and extrapolating the existing efficacy data to other tumor types are major undertakings, particularly since the bevacizumab doses and schedules varied from one trial to the next (Table 3.8). Intriguingly, efficacy and toxicity of bevacizumab with

Use of Epidemiologic Data in Risk Assessment Hazard Identification

Nonetheless, epidemiologic data have played a central role in some risk assessments, e.g., lung cancer environmental tobacco smoke (US EPA 1992a) and lung cancer indoor radon (US EPA 1992b). In its 1992 risk assessment, the Environmental Protection Agency classified environmental tobacco smoke as a class A carcinogen (i.e., a carcinogen for which definitive human carcinogenicity was available). The report noted that the data from active smokers, in combination with an understanding of mechanisms and dose-response relations, were sufficient for this classification. However, a principal basis for the classification was the result of a meta-analysis of the epidemiologic studies on lung cancer risk in never-smoking women married to smokers. The agency's analysis was also careful to consider potential sources of bias affecting the findings of the epidemiologic studies. In the example of radon, there is convincing evidence on human carcinogenicity from epidemiologic studies of radon-exposed...

Anogenital squamous cell carcinoma

There is a threefold increase in incidence in testicular germ cell tumours in homosexual HIV positive men. Seminoma is much more common than teratoma. Lung cancer of all histological types, non-melanomatous skin cancers, angiosarcomas and paediatric leiomyosarcomas may all be increased in HIV infection. Lung cancers occur at an earlier age and have a poorer prognosis in the HIV positive population.

Conclusions And Recommendations

These encouraging phase I-II data have provided the foundation for a major pivotal phase III program, and major clinical trials have been initiated in patients with advanced pancreatic cancer, malignant glioblastoma, small-cell lung cancer, nonsmall-cell lung cancer, gastric cancer, ovarian cancer, and breast cancer. All of these trials are looking at hard clinical end points, such as survival and disease progression, and, when completed, should provide the first step toward identifying the potential clinical use of this class of agents.

Neoplastic involvement of the brachial plexus

Extension of lymphoma Metastatic breast cancer Pancoast tumor (usually lung cancer) Tumorous brachial plexopathy is an early sign in lung cancer, and a late sign in breast cancer. Extension of the tumor mass into the epidural space may occur and cause additional spinal signs.

Obstruction of superior vena cava

Conventionally, obstruction of the superior vena cava has been regarded as an oncological emergency requiring immediate treatment. If it is the first presentation of malignancy, treatment will be tempered by the need to obtain an accurate histological diagnosis to tailor treatment for potentially curable diseases, such as lymphomas or germ cell tumours, and for diseases such as small cell lung cancer that are better treated with chemotherapy at presentation. In advanced disease, patients need relief from acute symptoms of which dyspnoea and a sensation of drowning can be most frightening and high dose corticosteroids and radiotherapy or chemotherapy should be considered. In non-small cell lung cancer palliative radiotherapy gives symptomatic improvement in 60 of patients, with a median duration of palliation of three months. Up to 17 of patients may survive for a year. If radiotherapy is contraindicated or being awaited, corticosteroids alone (dexamethasone 16 mg day) may give relief....

Eugene KennedyMD and Michael A ChotiMD

Colorectal cancer (CRC) is the fourth most common malignancy in the United States with 147,500 new cases in 2003, ranking behind lung, breast, and prostate cancer. With 57,100 deaths, it is the second to lung cancer as the leading cause of cancer related deaths (Jemal et al, 2003). Large bowel cancer can be further divided by the anatomic location of the tumor into colon and rectal cancer. Colon cancers are those that arise within the portion of the large bowel that is within the peritoneal cavity, from the cecum to the peritoneal reflection where the large bowel becomes the rectum. The distinction from rectal cancer, although seemingly somewhat arbitrary, is important to make for several reasons, including the clinical presentation, the operative management, and the type of adjuvant therapy offered. Of all large bowel cancer, the colonic site makes up approximately 70 . Like rectal cancer, colon cancer management requires a mul-tidisciplinary team approach in order to optimize...

David C Miller BS David K Ornstein MD Gerald L Andriole MD

Prostate cancer is the most commonly diagnosed noncuta-neous malignancy in American men and is exceeded only by lung cancer as a cause of cancer death among United States males.1 Estimates for 1998 indicated that over 180,000 men would be diagnosed with carcinoma of the prostate in the United States and more than 39,000 would die from this disease.1 In addition, a substantial fraction of United States health care dollars are allocated to diagnosis and treatment of this disease.2 The identification of serum prostate-specific antigen (PSA) measurements as a valuable tool for early diagnosis of prostate cancer has resulted in widespread implementation of early detection as a means to reduce the morbidity and mortality of this cancer. The importance of improving diagnosis and treatment for men with prostate cancer is unchallenged however, the most efficient way of accomplishing this has been debated.

Cancers of the Respiratory Tract

Macchiarini et al. (79) first assessed whether the degree of angiogenesis correlates with metastasis in nonsmall-cell lung cancer (NSCLC). They determined intratumoral microvessel density in a series of 87 patients with initial tumor stage T1N0M0 who underwent radical surgery. The 22 patients who developed recurrence during the follow-up period had tumors with a statistically higher vascularization, compared to those alive and disease-free. Seven subsequent studies (80-86) investigated the prognostic significance of vascularization in NSCLC, and, in all the series, the patients with radically resected, highly vascularized primary tumors had poorer prognosis, compared to those with low angiogenic tumors (Table 4). Of particular interest were the studies by Apolinario et al. (84), suggesting that the prognostic value of neovascularization is more relevant in patients with stage II disease, and that the degree of angiogenesis was not related to the other biological (p53, bcl-2, and bax...

Information on Potential Exposure to Environmental Agents

Information on exposures to environmental agents can be used in evaluating the risk to health represented by noninfectious diseases, injuries, and certain infectious diseases. For example, measurement of airborne particulates is useful in assessing risks related to certain pulmonary disorders (e.g., asthma and lung cancer). Information on vectors that may carry agents of infectious disease (e.g., ticks as vectors for Lyme disease and Rocky Mountain spotted fever, mosquitoes as vectors for viral encephalitides, and raccoons as vectors for rabies) is important in evaluating the risk of infection. Information on exposures to known risks supports the development and implementation of rational public health interventions (e.g., ATSDR's Hazardous Substances Emergency Events Surveillance System provides information on the public health consequences associated with the release of hazardous substances) (CDC 1994e). In addition, information on exposures provides the basis for issuing alerts to...

Discussion And Conclusions

While it is known that for those exposed to arsenic occupationally through inhalation, smoking increases the arsenic-associated risk for developing lung cancer, it is unclear whether smoking has a similar modifying effect in relation to carcinogenicity of ingested arsenic. Several studies do suggest that smoking influences methylation, but findings require confirmation in different populations, and the impact on cancer risk and attributable cases is unclear. Similarly, genetic factors also appear to influence methylation capacity, but the data are sparse. Liver disease or infections that alter liver function are also suspect modifying factors. Attention should be paid to those who are taking medications that may compromise liver function.

Clinical Significance or Insignificance of Prostate Cancer

Length bias has been documented in randomized trials of mammography for breast cancer and chest radiography with sputum cytology for lung cancer. More recently, it has been associated with digital rectal examination (DRE) screening for prostate cancer.7 There are consistently more cases detected in the screened group than in the control group. In the case of lung cancer, virtually all these excess cases of lung cancer were localized surgically operable lesions yet, in the randomized screening trials for lung cancer, virtually identical numbers of lung cancer deaths were observed in the screened arms versus the controlled arms. In two of these studies, there was an increased but not statistically significant number of deaths in the screened group. This illustrates that length biases do exist and do matter in terms of quality of life.

Antiangiogenic Therapy Approach in Cancer Patients

Solid tumors account for more than 85 of cancer mortality. Tumor angiogenesis is a rational target for therapy given the dependence of solid tumor growth and metastasis on blood vessels 5,27,53,108,109 . Strategies have been pursued to inhibit neovascularization, or destroy existing tumor vessels. These include direct targeting of endothelial cells, supporting perivas-cular cells, or indirect targeting by inhibition of proangiogenic growth factors release by cancer or stromal cells. Unlike preclinical studies in mice, no randomized Phase III trial has demonstrated a survival benefit with currently available targeted (e.g., anti-VGEF) AAs used as monotherapy. However, the addition of a VEGF-specific antibody, bevacizumab (Avastin, Genentech), to current cytotoxic regimens led to improved outcomes in previously untreated colorectal, breast, and lung cancer patients and in previously treated colorectal cancer patients 110,111 .

Reducing Behavioral Risk Factors

Epidemiologic studies have been successful in identifying and quantifying modifiable, behavioral risk factors (e.g., cigarette smoking, lack of physical activity, sexual practices, illicit drug use, lack of screening utilization) for many diseases. These risk factors can be considered voluntary since, for Environmental tobacco smoke (ETS) has been shown to be a cause of lung cancer in nonsmokers through approximately 35 epidemiologic studies (US Environmental Protection Agency US EPA 1993). Based on these data, federal, state, and local governments in the United States and other countries have enacted policies to limit or prohibit smoking in workplaces and other public places. These policies have not only protected the health of non-smokers but have also resulted in other possible benefits including increased cessation rates among smokers and cost savings to employers (Brownson et al. in 1997b).

Motor neuropathy or motor neuron disease syndrome

Motor neuron disease syndrome is associated with several cancer conditions and can exhibit different combinations of lower and upper motor neuron signs. One type associated with anti-Hu antibodies is relentlessly progressive and involves mostly lower motor neurons and encephalopathy. Another lower motor neuron syndrome is associated with lymphoma. A syndrome of upper and lower motor neuron signs resembling ALS is linked to numerous tumors (lymphoma, ovarian, uterine, breast, non-small cell lung cancer). Finally, an upper motor neuron syndrome has been reported with breast cancer.

Phase Iii Trial Design

The adjuvant setting may ultimately be where Als provide the greatest benefit however, identifying the efficacy of the AI in this setting w ill require a commitment of patient resources, time, and money. The efficacy of adjuvant therapy, following complete surgical resection of a tumor, has been proven for breast cancer, colon cancer, and melanoma. The rationale for adjuvant therapy is to eradicate microscopic disease. In designing a clinical trial in the adjuvant setting for a particular disease, it is important to understand the natural history of patients rendered free of disease by surgery, radiation, and or chemotherapy. As an example, response rates of 85-95 , including 50-60 CRs, can be achieved with combination chemotherapy in limited-stage, small-cell lung cancer (50). Unfortunately, the median survival remains between 12-16 mo. Patients attaining a CR to standard cytotoxic chemotherapy could be considered for a trial randomizing patients between an AI or placebo. The number...

Summary and Discussion

We have presented for discussion a broad-based review of the utility of adenoviral vectors in animal models of lung cancer. Since this entire compilation is devoted to Ad-gene therapy, we have particularly embellished the sections on animal models of disease, especially as they pertain to lung and prostate cancer. These examples illustrate that the development of our approaches may need to be disease specific, especially with respect to targeting and mode of delivery. From this review, it is evident that to realize the full potential of cancer gene therapy, advances need to be made on a number of fronts. Not only do we need to construct better Ad-vectors or more relevant animal models, we also need to incorporate emerging technologies to a useful purpose within the experimental design. For example, the pathway to human clinical trials may be better paved by an improved ability to gather interim surrogate measures of gene transfer and expression in animal models.

Pulmonary Neuroendocrine Tumors

Pulmonary NETs are similar to intestinal NETs and are unrelated to smoking.1 Pulmonary NETs account for 1 to 2 of all lung tumors. These tumors are thought to arise from neuroendocrine enterochromaf-fin cells located in the bronchial mucosa. Pulmonary NETs vary from well-differentiated bronchial tumors to the most malignant small cell lung cancer.12 Pul

Animal Models of Human Prostate Cancer

After lung cancer, cancer of the prostate (CaP) is the second most common cause of cancer death in American males. A latent disease, many men have prostate cancer cells long before overt signs of the disease are apparent. The annual incidence of CaP is over 100,000 in the United States, of which over 40,000 will die of the disease. Nearly a third of patients present with locally advanced or metastatic disease, and androgen deprivation therapy forms the basis of conventional therapy for the majority of these patients. However, currently available approaches for advanced CaP are not curative 137 , primarily because the cells lose their dependence on androgenic stimulation. The mechanisms of progression of CaP cells to hormone independence under androgen ablation therapy remain unclear. To investigate the factors and mechanisms that underlie the development of androgen resistance and metastasis, reliable in vivo models that mimic human CaP progression are essential. Moreover, it is...

Future Screening Modalities

Are released through the pancreatic ducts into pancreatic juice, duodenal fluid, stool, and, to a lesser extent, into the blood. Although all of these secondary sources can be sampled, an ideal diagnostic marker of pancreatic neoplasia would be measurable in serum. Unfortunately, in the setting of early invasive PC, existing serum markers are often normal. This suggests that in order to detect pre-invasive lesions of the pancreas, a more direct sampling of the pancreas will be required. Pancreatic juice can be collected during routine upper GI endoscopy after secretin stimulation. Higher levels of cancer DNA and proteins make pancreatic juice a potentially optimal specimen to use when screening high risk patients for PC, analogous to sputum for lung cancer or nipple aspirates for breast cancer.

Classic Phase I Clinical Trial Design

As suggested above, the typical phase I clinical trial includes a very heterogeneous patient population in terms of prior treatment and underlying malignancies. Phase I clinical trials can be disease-directed, if significant preclinical activity is observed in tumor xenograft models. This type of disease-directed trial will optimally define the toxicity and pharmacology of a new drug(s) in a homogenous patient population, but, depending on the prevalence of the disease (i.e., breast or lung cancer vs cholangio-carcinoma), patient accrual to the trial may be slow, and, as a result, delay the identification of the MTD.

New Targets for Antisense Therapy of Cancer

Survivin is another IAP family member. Survivin is overexpressed in a large proportion of human cancers, providing evidence that altered expression of these proteins occurs during tumorigenesis (58,59). In colorectal, gastric, breast, bladder, and lung cancers, as well as in diffuse large B-cell lymphoma, survivin expression is associated with shorter survival (60-67). In neuroblas- toma survivin expression correlates with higher stage of disease (68). Interestingly, survivin is expressed in a cell cycle-dependent manner with highest levels in G2 M and rapid downregulation following cell-cycle arrest (69). At the beginning of mitosis, survivin associates with the mitotic spindle, and disruption of this interaction results in a loss of its antiapoptotic function (69). It has been suggested that survivin frees cyclin-dependent kinase 4 (CDK4) from the CDK inhibitor pi6INK4 CDKN2. CDK4 then translocates into the nucleus, where it initiates the S-phase of the cell cycle (70). The...

Concepts of Health and Disease

Yet where the structural tier of health and disease is concerned, it is worth remembering that even a completely normal diagnostic test does not definitively rule out the possibility of disease. The bone radiograph may be initially normal, and it is only a week later, after demineralization has taken place and some periosteal reaction has formed adjacent to the fracture that we are able to recognize a nondisplaced hairline fracture. Even our most sophisticated imaging studies may not show us the pathology. For example, a patient with severe psychosis may have a normal magnetic resonance imaging (MRI) exam of the brain. Conversely, there is no guarantee that every patient with an abnormality of diagnostic testing actually has the disease. A solitary pulmonary nodule may represent a granuloma, and not a lung cancer at all.

Jnc Vi Life Style Modifications

(2.4 g sodium or 6 g sodium chloride) Maintain adequate intake of dietary potassium (approximately 90 mmol d) Maintain adequate intake of dietary calcium and magnesium for general health Stop smoking and reduce intake of dietary saturated fat and cholesterol for overall cardiovascular health

Secondary prevention of peripheral vascular disease

Effective reduction of the risk of cardiovascular disease depends on coordinated and stringent modification of identifiable risk factors to prevent progression or new disease and the use of drugs to correct existing abnormalities. Stopping smoking, correction of hyperlipidaemia and hypertension, and optimisation of diabetic control are the cornerstones of secondary prevention of cardiovascular disease. Lesser benefits are also likely to accrue through weight reduction in obese patients, the institution of regular exercise, and dietary modification. Additional risk factors have been identified but are uncommon and their treatment is of unproved value. Cigarette smoking Cigarette smoking contributes to a third of all deaths from coronary artery disease, doubles the risk of stroke, and is almost ubiquitous among patients with peripheral vascular disease. Synergy between smoking and other risk factors substantially increases the risks of cardiovascular death associated with these factors....

Degenerators of cells

The biotoxicity of pyridine alkaloids is well studied and the toxicity of nicotine is one of the best examples of the very active alkaloids study area. Aydos et al.478 have studied 20 rats injected daily with nicotine at doses 0.4 mg 100g-1 of body weight during 3 months and made comparisons to a control group of 20 rats. The researchers concluded that ultra-structural alternations in rats exposed to nicotine occurred. Aydos et al.478 underlined the particularly detrimental effects of nicotine on germ cells, peritubular structures and Sertoli cells. The germ cells were degenerated, and spermatids retained excess cytoplasm and accumulated electron-dense lipid droplets in the cytoplasm. Moreover, the results of Aydos et al.478 proved that the acrosomes in rats exposed to nicotine were irregular and abnormally configured. It is not difficult to interpret these results as evidence of active nicotine toxicity. Moreover, this chronic toxicity is reported also by Sener et al.479, who have...

Therapy of Distal Disease

When mild distal disease is not controlled with this approach, or the disease is more severe, combined rectal 5-ASA (4 g d enema) and oral 5-ASA (2.4 to 4.8 g d) may prove effective. Alternatively, the addition of a hydrocortisone enema or hydrocortisone foam may be given once daily in addition to the oral 5-ASA therapy for a period of 3 to 4 weeks. If remission is not accomplished with this regimen, then prednisone 40 mg d for 2 to 4 weeks, in addition to oral 5-ASA, maybe used. Once symptoms are controlled, pred-nisone may be reduced by decreasing the daily dose by 10 mg each week down to 20 mg d, then reducing the daily dose by 5 mg per day each week or 2 weeks until the prednisone is stopped. Oral 5-ASA therapy (2.4 to 4.8 g d) may be continued for long term maintenance therapy. For the patient who responds to oral prednisone but promptly worsens as the dose is reduced despite maintenance therapy with 5-ASA, then azathioprine (AZA) or 6-mercaptopurine (6-MP) can be added. We check...

Therapy of Extensive Disease

For moderate symptoms, we start high dose oral 5-ASA with Asacol at 4.8 g d (may be available as 800 mg tablets) or Pentasa at 4.0 g d (available as 500 mg capsules) if the symptoms do not improve in a week, prednisone should be started at 40 mg d as a single morning dose. Once symptoms come under control, the prednisone can be tapered, with reductions by 10 mg d each week down to a dose of 20 mg d, and with reductions of 5 mg d each 1 to 2 weeks thereafter until prednisone is discontinued. If there is initial improvement but then symptomatic worsening while tapering prednisone or within a few weeks of stopping, the dose of prednisone can be increased again until symptoms improve and then tapered more slowly. For the patient who again flares with the second prednisone taper, the pred-nisone may be increased to the dose that controlled the symptoms, with AZA 2 to 2.5 mg kg d or 6-MP 1 to 1.5 mg kg d added. The prednisone may again be tapered after another 2 months. For those not...

Emboli and palpable pulses

The toe became necrotic but was not amputated. At first it was believed that the necrosis was full thickness and that the toe would autoamputate through the interpha-langeal joint, but the necrosis was more superficial than first thought. The toe was treated conservatively with outpatient debridement by the podiatrists and systemic antibiotics and aspirin, and healed in 1 year. He continued to smoke heavily despite being referred to the smoking cessation clinic.

Blood Pressure Management

As described in the corresponding section, patients with type II diabetes are particularly susceptible to lipid abnormalities. Lipid management strategies should be aimed at reducing LDL cholesterol, raising HDL cholesterol, and lowering triglycerides. Healthy lipid levels have shown to reduce the risk of cardiovascular complications and mortality. Lifestyle changes including nutritional changes, physical activity, smoking cessation, and weight loss should be considered as initial strategies to achieve lipid levels. Drug therapy including statins, fibrates, and niacin is indicated when lifestyle changes alone are ineffective.

Structural Distribution Models

Besides the mean difference, other contrasts between the distributions of Y(1) and Y(0) can be modeled. One then relies on the randomization assumption to demand equality of the ( Y(1), Y(0), Z) distribution between arms rather than mere equality of means. Particularly for right censored response data, comparing estimated distributions via Kaplan-Meier curves rather than via means is a natural approach. Structural failure time models based on accelerated failure time models were introduced by Robins and Tsiatis (1991). Mark and Robins (1993) use these to estimate the effect of smoking cessation in the MRFIT study which randomizes over a life style intervention targeting multiple risk factors. Greenland and Robins (1994) compared high and low dose AZT in a trial which did randomize over the high and low dose, but where differential administration of a third drug (PCP prophylaxis) over the two arms had taken place post randomization. White et al. (1999) and White and Goetghebeur

Scope of clinical problem

Although the primary pathophysiology of PAD is impaired perfusion to the lower extremity, all conventional PAD treatments such as antiplatelet therapy, angiotensin-cascade antagonists, HMG-CoA-reduc-tase inhibitors, and smoking cessation target general atherosclerotic risk factor reduction (especially smoking cessation). In selected patients, structured exercise (in IC) and limb hygiene (in CLI) are of benefit. At present, pharmacological therapies used in PAD do not improve perfusion. Pentoxifylline, although widely prescribed in the United States, has little or no clinical benefit (6). Cilostazol, a phosphodiesterase inhibitor, offers some clinical efficacy, but its safety in patients with ventricular dysfunction remains in question, and the US Food and Drug

Factors Affecting Noncardiac Risk

Testing of pulmonary function may be indicated on the basis of physical findings (e.g. cough, wheezing, dyspnea on exertion, rales or rhonchi) or a history of cigarette smoking. Limited pulmonary reserve may be revealed by observing the patient for dyspnea while he or she is climbing one or two flights of stairs. Forced expiratory volume can be directly measured with a handheld spirometer whenever there is a question of possible pulmonary compromise.40 Once identified, patients with pulmonary insufficiency see 8 4 Pulmonary Insufficiency may benefit from a preoperative program that includes smoking cessation,9 use of bronchodilators, physiotherapy, and specific antibiotics.

Supplemental Reading

Brant SR, Picco MF, Achkar JP, et al. Defining complex contributions of NOD2 CARD15 gene mutations, age at onset, and tobacco use on Crohn's disease phenotypes. Inflamm Bowel Dis 2003 8 281-9. Brown LM, Devesa SS. Epidemiologic trends in esophageal and gastric cancer in the United States. Surg Oncol Clin N Am 2002 11 235-56. Burns DM, Garfinkel L, Samet JM. Changes in cigarette related disease risks and their implications for prevention and control. NCI Smoking and Tobacco Control Monographs 1997 Feb. Calam J, Baron JH. Pathophysiology of duodenal and gastric ulcer and gastric cancer. BMJ 2001 323 980-2. Cosnes J, Beaugerie L, Carbonnel F, et al. Smoking cessation and the course of Crohn's disease an intervention study. Gastroenterology 2001 120 1093-9. Cosnes J, Carbonnel F, Beaugerie L, et al. Effect of cigarette smoking on the long term course of Crohn's disease. Gastroenterology 1996 110 424-31. Cottone M, Rosselli M, Orlando A, et al. Smoking habits and recurrence of Crohn's...

What Is Community Level Variation and Why Does It Matter

Imagine a hypothetical community trial in which a woefully underfunded and wholly ineffective smoking-cessation program in community A is compared with no intervention at all in community B. For simplicity, also assume that community A's program is evaluated based on a comparison of quit rates in a random sample of smokers in each of the two communities after the intervention in community A has been in place for a while. What is the probability of finding a statistically significant difference in quit rates between the two communities error when the null hypothesis is true, usually chosen to be 0.05. In fact, the chance of finding a significant difference is probably considerably higher than a. The reason is related to a very basic idea in epidemiology namely, that diseases do not occur at random in populations but vary systematically in relation to personal characteristics, time, and (importantly) place. Often such geographic differences are the source of hypotheses, and often they...

Community Based Coalitions

The appeal of places of worship as settings for health promotion and disease prevention is based on experience suggesting that such settings are receptive to health-related programs, have access to large numbers of persons from all socioeconomic and ethnic groups, have effective communication and meeting facilities, and are oriented to volunteerism (Lasater et al. 1990 1991 DePue et al. 1990). Since its creation in 1989, the Heart, Body, and Soul Program has evolved in scope to include programs targeted against heart disease, smoking, obesity, violence, crime, substance abuse, and tuberculosis, as well as the promotion of youth education, completion of schooling, and career development. Examples of the effectiveness of this approach include significantly improved rates of identification, care, and control of hypertension, as well as concomitant decreases in related morbidity and mortality and significant improvement in smoking cessation (Levine et al. 1979, 1990 Morisky et al. 1983...

Mary Lawrence HarrisMD

Ulcerative colitis (UC) and Crohn's disease (CD), collectively referred to as inflammatory bowel disease (IBD), are diagnosed most commonly in patients in their childbearing years. The incidence of CD in young adults is increasing, whereas the incidence of UC affecting patients in their reproductive years has remained stable. The etiology of IBDs is unknown, but clearly genetic factors and tobacco use have been implicated. Women routinely express concern about sexual intimacy, self-esteem, marriage, fertility, offspring inheritance of IBD, role of disease activity during pregnancy, safety of medications, and, finally, outcome or general health of the fetus. The most important issues for the patient are education and optimal timing of the pregnancy.

The Coeffect Of Alcohol And Tobacco Smoking

Alcoholics are commonly heavy smokers. There is a synergistic effect of alcohol consumption and smoking on cancer development, with long term ethanol consumption enhancing the mutagenicity of tobacco-derived product 24 , The combined ingestion of ethanol resulted in a significant formation of smoke-related DNA adducts in the esophagus and in their further, dramatic increase in the heart. Thus ethanol consumption increases the bioavailability of DNA binding of smoke components in the upper digestive tract and favors their systemic distribution. Formation ofDNA adducts in the organs examined may be relevant in the pathogenesis oflung and esophageal cancers as well as in the pathogenesis of other types of chronic degenerative diseases, such as chronic obstructive pulmonary diseases and cardiomyopathies 29 , Numerous studies have indicated a correlation between ethanol intake and cigarette smoking in heavy drinkers 30 , On a pharmacological basis, an ethanol-induced potentiation of...

Risk Perception and Risk Communication

Risk communication is a specialized communication strategy used by epidemiologists who work in health agencies or industries to improve the use of risk assessments in decision-making. Many of the strategies described elsewhere in this chapter promote public awareness of health issues, especially public concern regarding the health aspects of behaviors such as tobacco use, diet, and exercise. In contrast, risk communication can be considered a strategy to decrease the public's concern about certain health risks, most often those related to environmental exposures.

Management of Aortic Disease and Associated Urologie Problems

On occasion, surgeons may encounter aorta-iliac aneurysms, which coexist with genitourinary neoplasms of the prostate, bladder or kidney. Both processes predominantly occur in the same age group, have a male predominance and may have one or more risk factors in common such as tobacco use. In addition, both organ systems occupy the retroperitoneum and are anatomically in close proximity.

Michael F PiccoMD PhD

Cigarette smoking is the most important preventable cause of mortality in the United States. Despite the common knowledge of numerous adverse effects, it is sad that so many young people start smoking. Although smoking rates seem to be declining, in 1998 26 of adult men and 22 of adult women were current smokers. Smoking has been linked to as many as 50 of all deaths among current smokers (Burns et al, 1997). Importantly, tobacco (nicotine) is an addictive substance with a clear psychological and physical withdrawal syndrome.

Carbon Monoxide Poisoning

The lethal effect of carbon monoxide (CO) is well known. This colorless, odorless gas occurs in cigarette smoke, engine exhaust, and fumes from furnaces and space heaters. It binds to the ferrous ion of hemoglobin to form carboxyhemoglobin (HbCO). Thus, it competes with oxygen for the same binding site. Not only that, but it binds 210 times as tightly as oxygen. Thus, CO tends to tie up hemoglobin for a long time. Less than 1.5 of the hemoglobin is occupied by carbon monoxide in most nonsmokers, but this figure rises to as much as 3 in residents of heavily polluted cities and 10 in heavy smokers. An atmospheric concentration of 0.1 CO, as in a closed garage, is enough to bind 50 of a person's hemoglobin, and an atmospheric concentration of 0.2 is quickly lethal.

Chronic Obstructive Pulmonary Diseases

Histamine and other inflammatory chemicals that cause intense bronchoconstriction and sometimes suffocation (see p. 828). The other COPDs are almost always caused by cigarette smoking but occasionally result from air pollution or occupational exposure to airborne irritants. Beginning smokers exhibit inflammation and hyper-plasia of the bronchial mucosa. In chronic bronchitis, the cilia are immobilized and reduced in number, while goblet cells enlarge and produce excess mucus. With extra mucus and fewer cilia to dislodge it, smokers develop a chronic cough that brings up sputum (SPEW-tum), a mixture of mucus and cellular debris. Thick, stagnant mucus in the respiratory tract provides a growth medium for bacteria, while cigarette smoke incapacitates the alveolar macrophages and reduces defense mechanisms against respiratory infections. Smokers therefore develop chronic infection and bronchial inflammation, with symptoms that include dyspnea, hypoxia, cyanosis, and attacks of coughing.

Avoid Predefined Groupings

For example, rather than ask the patient to classify their smoking habit as in Smoker (never, quit over 1 month, < - pk day, - to 1 pk day, > 1pk day) have them enter the number of years they've smoked, their average pack per day consumption, and whether they are current smokers. Avoiding pre-defined groupings gives us much greater flexibility and allows us to use metric variables rather than categorical ones, paving the way for the use of more sensitive statistics. We can measure exposure to cigarette smoke in pack years or we can classify smokers as never, quit over 2 months, < -pk day,- to 2pk day, > 2pk day.

History And Physical Examination

According to the American Heart Association, smokers made up a 40 smaller percentage of the U.S. population in 2003 than they did in 1965.9 Nevertheless, approximately one third of surgical patients are still smokers. Smoking is clearly a risk factor for perioperative complications,10 including pulmonary complications, circulatory complications, and an increased incidence of surgical site infection. Numerous mechanisms contribute to the deleterious effects of smoking smoking inhibits clearance of pulmonary secretions, adversely affects the immune system and collagen production, and contributes to wound hypoxia (thereby increasing susceptibility to infection).11 Some studies have suggested that even passive smoking can reduce blood flow velocity in the coronary arteries of healthy young adults.12 A 2002 trial demonstrated that preoperative smoking cessation reduced the incidence of postoperative complications from 52 to 18 .10 A 2003 study reported similar results patients who stopped...

Loma Linda University Experience

From April 1980 to November 1997, 69 octa- or nonagenarians had aortic aneurysm repair at Loma Linda University Medical Center. There were 56 patients who had elective aneurysm repair and 13 patients who had ruptured aneurysm repair. Mean age was 83 years (range 80-92 years). In the nonruptured group, there were 39 (69.6 ) males and 17 (30.4 ) females. In the ruptured group, 9 (69.2 ) were male and 4 (30.8 ) were female. Within the total group, hypertension was present in 65 (94 ) patients. Cardiac symptoms such as angina, prior myocardial infarction or history of congestive heart failure were noted in 63 (91 ) patients. One (2 ) of these elective patients had severe asymptomatic carotid stenosis and had uneventful endarterectomy before aneurysm repair. Five (9 ) other patients in the elective group were found to have asymptomatic moderate internal carotid artery stenosis. Lower extremity vascular disease ranging from mild claudication to prior major amputation was present in 30 (43 )...

Interview And Clinical Examination

Patients diagnosed with liver enlargement were further interrogated regarding any past history of jaundice, parasite expulsion, history of taking alcohol or other hepato-toxic drugs. In regard to the respiratory system, if the participant did not volunteer any information concerning the presence of a respiratory problem, they were then specifically asked whether they had any cough or breathing difficulty. Crepitations were determined by auscultation and were defined as the presence of any chest sounds including rals or rhonchi. Participants were also asked if they were current or past smokers.

Gastrointestinal Neoplasms

The associations between tobacco and cancers of the stomach and colon are not as clear. The risk for gastric cancer is higher among smokers, and smoking does increase the risk of squamous metaplasia of the gastric cardia, which is likely a premalignant condition (Brown and Devesa, 2002). Tobacco is also associated with an increased risk of colonic adenomas (Potter, 2001), which lead to colorectal cancer, but a direct link of smoking to AC of the colon has been difficult to establish.

Patients And Methods

Forty-one BD patients, 25 male and 16 female, aged from 19-46 years, registered at the BD Clinic at Saddam Medical City and fulfilling the International Study Group Criteria (ISGC) for the diagnosis of BD7 and 37 healthy individuals, 19 males and 18 females, with an age ranging from 2538 years, participated in the study. Control individuals had no history of serious illness, were normal on physical examinations and had no history of sulphonamide allergy or G6PD deficiency. Smokers, drinkers and those taking medications in the last week were excluded. All subjects gave their informed consent. The study was approved by the ethics committee.

Clinical Box 42 Marijuana Antagonist Blocks Munchies

Recently, researchers have described cannabinoid (CB) receptors, which are the GPCRs that recognize tetrahydrocannabinol found in marijuana. The CB1 receptor is found in areas of the brain that control appetite and addiction to smoking (tobacco), and this receptor may be responsible for the munchies experienced by marijuana smokers. The munchie connection led researchers to develop CBi-receptor antagonists in hopes that they would be useful as aids for weight loss. One antagonist (rimonabant from Sanofi-Aventis) may soon be available as a diet pill and as an antismoking aid.

Free Transverse Rectus Abdominis Myocutaneous Flap

And fat necrosis, and are inherent to the procedure's secondary blood supply and volume constraints.57'66'73-76'84-86 These complications may impose prolonged wound healing and considerable delay in the therapeutic sequence. Although the free TRAM procedure requires greater technical proficiency and a slightly longer operating time, the flap has unparalleled vascular reliability and versatility, and is the flap of choice in high-risk patients. These include obese patients, smokers, and those patients with prohibitive scars or who have had prior radiation treatment.73-76

Materials And Methods

The standardized personal interview was used based on a structured questionnaire and was carried out by four public health nurses who were well-trained in the interview technique and questionnaire details. Information obtained from the interview included the duration of well water consumption, residential history, sociodemographic characteristics, cigarette smoking, alcohol consumption, physical activities, history of sunlight exposure, as well as personal and family history of hypertension, diabetes, cerebrovascular disease, heart disease, and cancers. Well water samples were collected during the interviews at home, acidified with hydrochloric acid immediately and then stored at 20 C until sub

Susceptibility To Transitional Cell Carcinoma

In a cohort study on urinary bladder cancer, mainly transitional cell carcinoma (TCC), in the BFD-endemic area, an increased risk was observed among patients affected with BFD as compared with the unaffected (Chiou et al., 1995). The odds ratio of developing urinary bladder cancer was around four-fold after adjustment for age, sex, cigarette smoking and cumulative arsenic exposure. In our most recent cohort study on TCC in the BFD-endemic and non-endemic areas, an increased risk of developing TCC was observed among patients affected with skin cancer than the unaffected. The odds ratio was around five-fold after adjustment for age, sex, cigarette smoking and cumulative arsenic exposure.

How will my clinician use my test results to determine whether I have osteoporosis

A Z-score is usually not helpful in making the diagnosis of osteoporosis. However, if it is particularly low (lower than -1.5), it is important for your clinician to evaluate you for conditions and illnesses that may be causing your bone loss associated with secondary osteoporosis. Such causes of secondary osteoporosis might include thyroid or parathyroid disease, cigarette smoking, excessive alcohol intake, problems with absorption from your gastrointestinal tract, or the use of medications known to be harmful to bone. Cigarette smoking

Clinical features and classification

Dysthymia covers persistent symptoms of depression that may not be severe enough to meet the criteria for major depression, in which depressed mood is present for two or more years. Such chronic forms of depression are associated with an increased risk of subsequent major depression, considerable social disability, and unhealthy lifestyle choices such as poor diet or cigarette smoking.

Toxemia and Preeclampsia Eclampsia

Pregnancy-induced hypertension (toxemia) is seen late in pregnancy and remains a major medical challenge. Five to 10 of pregnant women with toxemia may develop preeclampsia (hypertension plus proteinuria and nonde-pendent edema). Preeclampsia generally occurs during the second and third trimesters, and is most frequent in young primagravidas. Risk factors associated with preeclampsia include nulliparity, a positive family history, preeclamp-sia in a prior pregnancy, obesity, chronic hypertension or renal disease, diabetes mellitus, a multiple gestation pregnancy, low socioeconomic status, and cigarette smoking.

Incidence and Risk Factors

Most of the information regarding risk factors for abdominal aortic aneurysms is the result of large population based multivariate analyses in case-control studies and univariate analyses in prospective reports. Evidence has demonstrated that cigarette smoking is a significant and consistent risk factor for AAA formation. Other important risk factors include coronary artery disease, family history and hypertension. Characteristics such as diabetes and female gender have been identified as negative risk factors.

Complications and management of peptic ulcer surgery Early Complications

Cigarette smoking is detrimental to mucosal protective mechanisms and increases the likelihood that gastric ulcers will develop. Although these ulcers are generally amenable to ulcer treatment, they can occasionally be refractory to healing. This can be a difficult clinical problem in a patient with symptoms. If multiple biopsies have been negative for cancer, it is highly unlikely to be a malignant ulcer. As the ulcers will heal with cessation of smoking, this is the treatment of choice. The surgeon should be careful about offering a definitive ulcer operation in this patient group. Symptoms are often times not eliminated, and postgastrectomy complications are high.

Properties of the Coronary Microcirculation

A particularly important aspect of endothelial regulation of vasomo-tion is that endothelial-mediated vasodilation is abnormal in a variety of pathological conditions. These include atherosclerosis, hypercholester-olemia, diabetes, hypertension, cigarette smoking, and aging. The mechanisms underlying these abnormal endothelium-dependent responses have been the subject of substantial debate. Deficiencies of the substrate for eNOS, l-arginine, and the co-factor tetrahydrobiopterin have all been implicated, as well as the endogenous competitor of l-

Individual Level Outcome Data

Monoxide for smoking behavior, or blood pressure and cholesterol for cardiovascular disease prevention (Farquhar et al. 1990). In addition, if a cohort sample approach is used, there may be concern about whether repeated interviews about health behavior themselves constitute a co-intervention. Some studies (COMMIT 1995a Worden et al. 1994) have chosen to do less-intensive data collection for part of the sample to allow this possibility to be assessed.

Concommitant Cocaine And Ethanol Consumption

20-32 years of age) of varied socioeconomic status in 1987, and then to evaluate the relationship between lifetime cocaine use in 1987 and cardiovascular disease risk factors 5 years later. The longitudinal design, the cardiovascular focus of CARDIA, and the inclusion of essentially healthy individuals at baseline, provided a unique opportunity to assess the cardiotoxicity of chronic cocaine use. Results of the CARDIA study indicate that lifetime cocaine use experience in 1987, after adjustment for age, ethnicity, daily alcohol intake, cigarettes smoked per day, body mass index, sum of skinfolds, physical activity, and other illicit drug use, was not related to blood pressure, blood pressure difference, heart rate, or hypertension prevalence in cross-sectional analysis in either men or women. Regarding the long-term, multivariate relationships between lifetime cocaine use experience in 1987 and blood pressure, blood pressure difference, and heart rate in 1992, the data from CARDIA...

Clinical Presentation

Inflammatory abdominal aortic aneurysms occur predominantly in males in the 5th and 6th decades of life. The male to female ratio ranges from 15-6.5 1. Risk factors for atherosclerosis and the association with coronary artery (46-55 ) and peripheral vascular disease (24 ) occur with the same frequency as in patients with noninflammatory aneurysms. Nitecki et al has reported that patients with IAAA were more likely (17 versus 1.5 ) to have a family history of aneurysms and currently be smoking cigarettes.

Pet Studies Of Neurotransmitter Activity In Mild Ad

Few PET studies have so far been performed regarding transmitter and receptor dysfunction in AD. The cholinergic hypothesis has so far rendered PET ligands for nicotinic receptors, muscarinic receptors (Nordberg et al., 1995a, 1997, 1998), acetylcholinesterase activity (Iyo et al., 1997 Kuhl et al., 1999), and cholinergic terminal density (Kuhl et al., 1996). Detection of acetylcholinesterase activity and cholinergic terminal density by PET has also shown losses in activity in AD patients more pronounced than the impairment seen in glucose metabolism (Kuhl et al., 1996, 1999). It has been well established from autopsy brain studies that the neuronal nicotinic receptors are significantly impaired in AD (Paterson and Nordberg, 2000). It might therefore be useful to image the nicotinic receptors non-invasively in patients with MCI and mild AD. So far (S)(-)nicotine radiolabeled with nC has been used to target nicotinic receptors in vivo in human brain. A significant correlation has been...

Neurotransmission in the Somatic Nervous System

Just as a single main neurotransmitter serves the SNS, so does a single main receptor, an ionotropic, transmitter-activated channel called a nico-tinic ACh receptor (nAChr). When ACh binds to this receptor, the receptor's pore opens to permit ion flow, thus depolarizing the muscle fiber. The pore of a nicotinic receptor is large and permits the simultaneous efflux of potassium ions and influx of sodium ions. The molecular structure of nicotine, a chemical found in tobacco, activates the nAChr in the same way that ACh does, which is how this receptor got its name. The molecular structure of nicotine is sufficiently similar to ACh that nicotine acts as a ligand, fitting into acetylcholine receptor binding sites.

Drugs and Brain Development

National Institute on Drug Abuse (NIDA) estimates that about 25 percent of all live births in the United States today are exposed to nicotine in utero. Similar statistics on alcohol consumption by pregnant mothers are not available, but the effects of alcohol consumption in the etiology of fetal alcohol effects are well documented, as detailed in Chapter 7. The precise effects of drug intake on brain development are poorly understood, but the overall conclusion from current knowledge is that children with prenatal exposure to a variety of psychoactive drugs have an increased likelihood of later drug use (Malanga & Kosofsky, 2003). Many experts suggest that, although, again, poorly studied, childhood disorders such as learning disabilities and hyperactivity may be related to prenatal exposure to drugs such as nicotine or caffeine or both. Malanga and Kosofsky note poignantly that society at large does not yet fully appreciate the impact that prenatal drug exposure can have...

Medical Therapy Sequential versus Combination Therapy

Rectosigmoid Disease 5-ASA suppositories enemas 5-ASA enemas + oral 5-ASA (enemas + oral) + prednisone 5-ASA enemas + oral + prednisone + nicotine Stop 5-ASA and observe AZA 6-MP if steroid-dependent Surgery if poor quality of life Extensive Disease 5-ASA oral 5-ASA oral + enemas 5-ASA (oral + enemas) + prednisone 5-ASA (oral + enemas) + prednisone + nicotine Stop 5-ASA and observe AZA 6-MP if steroid-dependent Intravenous steroids Surgery if refractory to medications Cyclosporine if severe disease and surgery declined

Health and Social Considerations

Health is a complex and multidimensional concept that is related to a variety of physical, mental, and social factors (World Health Organization 1948 Aday 1994). Physical and mental health indicators tend to focus on the individual level, whereas social factors involve the larger context of society (e.g., health policies) (Aday 1994) (Figure 12-1). A broad vision of health and prevention recognizes the importance of individual risk factors (e.g., addiction to nicotine) and personal responsibility for health, environmental factors (e.g., air pollution), and social factors including housing, transportation, employment, civil rights, economic justice, and communications (Beau-champ 1976 Tesh 1981 Aday 1994). Similarly, health policy decisions are

Genetic approach to alkaloids

Ajmaline biosynthetic pathway-specific gene. Strictosidine synthase with cDNA and Genomic DNA (strl) has been isolated from Rauwolfia serpentina and Rauwolfia mannii527'540'541. This enzyme coded in cDNA has been isolated also from Catharanthus reseus542'543. Tryptophan decarbocylase endoded by cDNA has also been isolated from this plant and then described544. Moreover, Cane et al.533 recently discovered that the synthesis of the nicotine in the roots of Nicotiana tabacum is strongly influenced by the presence of two non-allelic genes, A and B. Hibi et al.545 have reported on putrescine N-methyltransferase isolated from the nicotine biosynthetic pathway coded by cDNA. Recent advances in cell and molecular biology of alkaloid biosynthesis have heightened awareness of the genetic importance.

Delayed Matchingtosample As A Paradigm For Assessing Cognition

Since our first report of the positive mnemonic action of nicotine in macaques in their performance of the DMTS task 30 , we have had the great fortune to work in collaborative studies with our colleagues in the pharmaceutical industry (and through our own modest drug discovery program) in the evaluation of a wide variety of potential drugs for the treatment of the cognitive impairment associated with neu-rodegenerative diseases and other psychiatric conditions. Though some of these data continue to be proprietary, a comprehensive database has been established that has allowed us to address several questions regarding aging, cognition, and the effects of drugs on these factors. One aspect of this work that has been of greatest surprise is the diversity of neurotransmitter substances involved in cognition. This diversity could reflect the concept that memory is represented by several distinct processes, and that different types of memory are relegated to different (but sometimes...

The Role of Environmental Factors

Like other autoimmune diseases, environmental factors have long been suspected in the etiology of the disease. For example, excess iodine intake is a risk factor for developing autoimmune thyroid diseases in both humans and animal models of AITD 33, 34 . Stress, drugs, and smoking can also contribute to the development of the disease. The common mode of action of all these factors is that they place stress on the thyroid 35 . It is possible that these environmental stresses can lead to thyroid injury, which may in turn release thyroid autoantigens or alter the immunogenicity of the thyroid antigens. Another set of environmental factors linked to AITD 36 and host immune responses is microbial infections, which can cause overexpression (e.g., heat shock proteins, MHC class II molecules, costimulatory molecules, etc.) and or altered expression of certain self-proteins (altered self). Presentation of these antigens by professional APCs could provide the necessary strength of signal or be...

Epidemiology and Risk Assessment

The value of epidemiologic data for risk assessment has been widely discussed (Graham 1995). Pundits argue that epidemiologic data are rarely relevant and too often flawed by poor quality and uncontrolled biases (Graham 1995). Epidemiologic studies have also been deemed uninformative given the weak associations anticipated for typical levels of exposure to many environmental agents. Proponents of epidemiology, while acknowledging the limitations of observational studies, advance its strengths the investigation of the effects of real exposures as received by the population the characterization of effect across the full range of susceptibility in the population and, above all, the direct relevance of epidemiologic evidence to public health (Hertz-Picciotto 1995 Burke 1995). The debate on the role of epidemiologic evidence in risk assessment has proceeded both generally and specifically, and risk assessment findings for individual agents, such as radon and environmental tobacco smoke,...

An Acetylcholine Synapse Examples of Drug Action

Figure 7-6 also shows two drugs that act on receptors for acetylcholine. As you learned in Chapter 5, nicotine's molecular structure is similar enough to that of ACh to allow nicotine to fit into the receptors' binding sites where it acts as an agonist. Curare acts as an antagonist by occupying cholinergic receptors and so preventing acetyl-choline from binding to them. organophosphates bind irreversibly to acetylcholinesterase and consequently are extremely toxic. Many insecticides and chemical weapons are organophosphates. Insects use glutamate as a neurotransmitter at the nerve-muscle junction but, elsewhere in their nervous systems, they have numerous nicotine receptors. Thus, organophos-phates poison insects by acting centrally, but they poison chordates by acting peripherally as well. choline synapses in the brain That depends on whether the substance can cross the blood-brain barrier. Some of the drugs that act on ACh synapses at the muscles can also act on ACh synapses in the...

Regulation of schizonticide activity

Drugs based on eserine, galanthamine, nicotine, lobeline and tubocurarine are also prominent. Two examples of drugs containing eserine are Anticholium and Pilo-Eserin. There are at least 20 different products based on this alkaloid. Nicotine is used in many products on the pharmaceutical market, for example Nicorette or Nicoderm. At least 20 different products are known to contain nicotine. These drugs are delivered in different forms. One of these is a transdermal plaster. Nicotine chewing gum and tablets are also available. These drugs are used especially to reduce nicotine cravings. The drugs that contain lobeline are, for example, Stopsmoke or Lobatox. These products are used for similar purposes as drugs that contain nicotine.

Paraneoplastic neuropathy

The pathogenesis of paraneoplastic neuropathies is unclear, but is believed to be the result of numerous auto-antibodies associated with cancer. The sensorimotor type has been associated with anti-CV2 antibodies. Demyelinating forms are more highly associated with lymphoma and Hodgkin's disease. Sensory neuronopathy is related to anti-Hu and other anti-neuronal antibodies, in the context of small cell lung cancer. Anti-Hu antibodies, especially in cases of lung cancer, may be detectable. Biopsies are rarely indicated, except for presumed vasculitic neuropathy.

Stratified Randomization

If you anticipate differences in the response to intervention of males and females, of smokers and nonsmokers, or on the basis of some other important cofactor, then you will want to randomize separately within each of the distinct groups. The rationale is exactly the same as discussed in the preceding section to ensure that in each group more or less equal numbers receive each treatment.

Ispinesib and related compounds

Sensitive non-small cell lung cancer, ovarian cancer, hepatocellular cancer, colorectal cancer, head and neck cancer, hormone-refractory prostate cancer, and melanoma. In the ongoing breast cancer study, women with locally advanced or metastatic breast cancer, receive ispinesib as monotherapy at 18mg m2 as a 1-h intravenous infusion for every 21 days. In an interim analysis of Stage 1 data from this two-stage trial, partial responses were reported in three of 33 evaluable patients. Maximum decreases in tumor size ranged from 46 to 68 , and the duration of response from 7.1 to 13.4 weeks. The overall response rate for all 33 evaluable patients was 9 with a median time to progression of 5.7 weeks. The adverse events were manageable, predictable, and consistent with the Phase I clinical trial experience with ispinesib, and ispinesib plasma concentrations were comparable to those observed in the Phase I clinical trial 11,16 .

Anovulation Is A Characteristic Feature Of Pcos. It Manifests As Menstrual Disturbance 80 Amenorrhoea Oligoamenorrhea

Patient With Hyperandrogenism

Weight gain that is primarily centripetal, especially if associated with extremity wasting, purple striae, easy bruisability, moon facies, and rubor, suggests the presence of Cushing's syndrome, and these patients should be appropriately screened using 24-hour urinary-free cortisol levels or a cortisol level following an overnight dexamethasone suppression test. Other information that should be sought includes the patient's awareness of her body fat distribution, as women with PCOS have a greater prevalence of abdominal obesity (29). Weight gain may also be associated with carbohydrate craving and evidence of postprandial reactive hypoglycemia, particularly in mid-afternoons. For example, Holte and colleagues found that although insulin resistance in obese women with PCOS was reduced by weight loss to similar levels as BMI-matched controls, these patients continued to demonstrate an increased early insulin response to glucose, which could stimulate appetite and persistent weight gain...

Surgical Treatment of Infected Aortic Aneurysms

Ruptured Mycotic Aneurysm

The clinical presentation of patients with mycotic aortic aneurysms is different than those patients presenting with contained rupture of an atherosclerotic aneu-rysm. In our experience,5 we noted that all patients with ruptured atherosclerotic aneurysm presented with symptoms of less than 24 hours duration. In contrast, all patients in the mycotic group had symptoms that ranged between two to six weeks with a mean of 3.5 weeks. History of sepsis was absent in all patients presenting with atherosclerotic aortic rupture whereas two-thirds of patients with mycotic aneu-rysms had history of sepsis. Abdominal, chest and or back pain was present in all patients regardless of etiology. The age at presentation was similar with a mean age of 73 years in the atherosclerotic group and 74 years in the mycotic group. There were no differences noted in the incidence of cigarette smoking, hypertension or the presence of chronic obstructive pulmonary disease. Coronary artery disease was present in...

Clinical Box 11 Why Doesnt Your Stomach Digest Itself

The weakening of these mucosal defense mechanisms results in ulcerations and eventually gastric ulcer disease. A variety of factors including excessive alcohol and tobacco consumption, stress, and nonsteroidal anti-inflammatory drugs such as aspirin can lead to erosion in the lining of the stomach. Additionally, there is also a positive correlation between Helicobacter pylori (H. pylori) bacterial infection and the incidence of gastric and ulcers of the small intestine. H. pylori produces large quantities of the enzyme urease, which hydrolyzes urea to produce ammonia. The ammonia neutralizes the gastric acid in the bacteria's immediate environment thus protecting the bacteria from the toxic effects of its normally toxic acid environment. It is remarkable how some cells find a way to survive even in the deadliest environment.

Intratumoral Microvascular Density

An equally important issue, as it relates to the assessment of an AI with serial biopsies for intratumoral MVD, is whether changes in these indices actually reflect the biologic activity of the AI. If serial tumor biopsies could be easily obtained, a more informative measure of AI activity may be evaluating changes in markers for endothelial cell proliferation, apoptosis, or angiogenic peptide, or integrin expression within the tumor. A potential problem inherent in this strategy is sampling error from one biopsy to another. A clinical setting in which it may be feasible to assess these types of markers is a pilot study in which patients must undergo a biopsy to confirm the diagnosis of cancer, prior to definitive surgery. In the interval prior to definitive surgery, patients could be enrolled on a study to assess the short-term biologic effects of an AI. Such study designs have been utilized successfully, including a recent report describing the effects of a new pure antiestrogen,...

Mayo Patients With Complex Aphthosis

A substantial number (almost 60 ) of patients had associated conditions relevant to their complex aphthosis problem (Table 2). Anemia and or hematinic deficiencies were present in 61 (25.0 ), gastrointestinal disease in 41 (16.8 ), and hematopoietic and immunodeficiency conditions in 12 (4.9 ) of patients. The onset was associated with smoking cessation in 10 (4.1 ), drug reactions in 8 (3.3 ), and chronic trauma in 6 (2.5 ) of patients. Twelve patients (4.9 ) had pseudo-Behget's disease, 8 patients (3.3 ) had cicatrizing oropharyngeal disease, while 4 (1.6 ) had erythema multiforme associated with complex aphthosis. It is notable that 25 patients with complex aphthosis and BD were seen during this same period. Smoking cessation

The Arbroath Multiple Disease Study

Previous surveys of patterns of environmentally sensitive respiratory disease in central Scotland had demonstrated a high mortality from lung cancer in residential areas of towns downwind of foundries.22-24 The town of Arbroath in eastern Scotland contained a central industrial area which housed a foundry. Due to concerns about the effects of this centrally located foundry on the health status of the surrounding community, it was decided to examine the spatial distribution of mortality arising for a range of diseases in the town area. Specifically the study aimed to test the hypothesis that deaths from bronchitis, gastric, oesophageal and lung cancer would be raised in areas affected by pollution from the foundry. For all residents in the town, information was extracted from the death certificates for the years 1966-76 on age, sex, address, occupation, and the causes of death. Certificates with any mention of lung cancer were used unless the cancers were secondary to a primary cancer...

Ruptured Abdominal Aortic Aneurysm

Tilson and Stansel evaluate clinical outcomes in 50 consecutive patients with abdominal aortic aneurysm (AAA) and 50 consecutive patients with aortic iliac occlusive disease (AIOD), with the demonstration that AAA patients are significantly (P < 0.05) more likely to be male, elderly, tall, to have large aortas even when normalized by body surface area and size ofartery. AIOD patients are significantly more likely to be female, middle-aged, smokers, and likely to undergo arterial reconstructions elsewhere. In this survey of a large number of emergency abdominal ultrasound examinations performed for ruptured aortic aneurysm, 7 of all those proven operatively to have extra-aortic blood had aneurysms measuring less than 5.0 cm in diameter. Aneurysms measured exactly 5.0 cm or less in 10 of this patient population. Other interesting findings from this study were that advanced pulmonary insufficiency, usually from heavy cigarette smoking, and diabetes appear to be predictors of small AAA...

Drug Lore And Dietetics

To over nine hundred other texts, and more than a thousand illustrations. Today, experts in Asian medicine hope that high-volume screening and rigorous clinical trials will demonstrate the value of traditional Chinese herbal remedies. For example, in 2003, the U.S. Food and Drug Administration approved a phase II trial to test the efficacy of one such remedy in treating non-small-cell lung cancer.

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