Investigators:

PI: Ira Goldfine
idg@itsa.ucsf.edu

Co-PI: Umesh Masharani
ubm@itsa.ucsf.edu

Study Coordinator: Christine Torok
Christine.Torok@ucsf.edu

Research question:
The study is designed to test the following primary hypothesis:

• Aerobic exercise training will improve insulin sensitivity in insulin resistant subjects through changes in the major cellular signaling pathways and and/or their regulators.
• Accordingly, the proposed study is designed to accomplish the following specific aims:
• Quantitate how exercise training improves insulin sensitivity and decreases cardiovascular risk factors in a general population of lean, nondiabetic, insulin resistant subjects. Effects on known cardiovascular risk factors including blood pressure and serum lipoproteins will be evaluated. Change in regional adiposity will also be measured
• Determine the effects of a program of regular aerobic exercise on in the insulin receptor signaling pathway. Biopsies of vastus lateralis muscle from insulin resistant subjects will be obtained before and after a hyperinsulinemic glucose clamp. This procedure will take place in the untrained state and after exercise training. We will measure changes in the insulin receptor and the activity of the major components of the intracellular insulin signaling pathway. We will also look intracellular proteins that regulate this signaling pathway.

Brief Background/Significance:
Type 2 diabetes involves both insulin secretory abnormalities and insulin resistance in peripheral tissues (1-2). Insulin resistance both precedes and contributes to the development of the disease (3). In addition, insulin resistance occurs in most subjects with impaired glucose tolerance, and some individuals with normal glucose tolerance (4). In these non-diabetic individuals, increased secretion of insulin is sufficient to maintain normoglycemia, although the resultant hyperinsulinemia is believed to play a role in causing hypertension, coronary artery disease and, hyperlipidemia (1).

There are numerous factors which can contribute to insulin resistance in an individual (2). Data from ethnic, family, and longitudinal studies suggest that insulin resistance can be inherited, and that it is an intrinsic feature of many patients with type 2 diabetes (5). There also are extrinsic causes by which insulin resistance can develop in an individual. Obesity and inactivity are common contributors to insulin resistance (6). In addition, an altered hormonal milieu (i.e. pregnancy, an excess of growth hormone, glucocorticoids, catecholamines etc.) can induce peripheral insulin resistance (7). It is not clear whether the various contributors to insulin resistance act through similar or distinct mechanisms, and in the majority of individuals the molecular basis of the resistance to insulin is unknown.

In insulin resistant subjects, decreased muscle glucose uptake accounts for nearly the entire decrement in insulin action(8). Therefore, studies utilizing the euglycemic clamp to demonstrate insulin resistance are in fact representing an impaired capacity for skeletal muscle to respond to insulin with appropriate elevations in the rate of glucose uptake. Diminished skeletal muscle glucose uptake has also been demonstrated in vitro in incubated muscle strips from insulin resistant subjects (9). Insulin binding to the extracellular (-subunits of the insulin receptor leads to autophosphorylation of specific tyrosine residues on the transmembrane (-subunits (10). This autophosphorylation activates the protein tyrosine kinase activity of the insulin receptor, which then phosphorylates key intracellular substrates and initiates the cellular mechanisms involved in enhancing glucose uptake and other responses (19). Various groups, including our own, have reported that insulin receptor tyrosine kinase activity is impaired in muscle, fat, fibroblasts, and other tissues in both diabetic (11,12) and non-diabetic (13), insulin resistant subjects. These latter subjects represent an important group in which to study the relationship between insulin receptor function and insulin resistance, since hyperglycemia and other metabolic abnormalities of the diabetic state are not present to potentially influence insulin receptor tyrosine kinase activity. We have recently employed a novel assay with improved accuracy and sensitivity to demonstrate that insulin resistance in non-diabetic Pima Indians is associated with an impaired capacity for skeletal muscle insulin receptor autophosphorylation (14). It appears that these skeletal muscle insulin receptor defects are heritable, as lean, pre-diabetic offspring of Type 2 diabetes patients have defects in muscle insulin receptor function (15).

The vast majority of cases of insulin resistance are not due to alterations in the insulin receptor gene (16). Several studies have provided potential mechanisms for impaired insulin receptor tyrosine kinase activity. We have recently shown that levels of the insulin receptor inhibitor, membrane glycoprotein PC-1, are elevated in muscle and fat from insulin resistant subjects (17), and overexpression of this protein in several cell lines produces insulin resistance and impaired IR kinase activity in culture. In healthy, non-diabetic, non-obese subjects the PC-1 content in skeletal muscle correlated negatively with whole body insulin action, and with skeletal muscle insulin receptor tyrosine kinase activity (18).

The insulins signaling system is under the control of other regulatory systems. Tyrosine phosphatases are increased in insulin resistant states. The protein kinase C family of serine kinases have been shown to directly phosphorylate the insulin receptor and have been implicated in muscle insulin resistance. The transcription nuclear factor (B (NF-(B) has recently been implicated in insulin resistance. The serine kinase, IKK(, which activates NF-(B is increased in insulin resistant muscle. Salicylates and thiazolidinediones (used to treat type 2 diabetes) inhibit IKK( restore insulin sensitivity. Also, the potent insulin sensitizer, adiponectin, inhibits endothelial NF-(B.

Both acute and chronic exercise can enhance insulin action in skeletal muscle (20). Evidence for the beneficial effect of a regular exercise training program comes from studies of trained athletes (20), from cross sectional studies correlating insulin sensitivity with degree of physical fitness, and from longitudinal studies of previously trained subjects undergoing an exercise regimen (21). Training studies have reported improvements in insulin-stimulated glucose disposal in normal subjects, and subjects with insulin resistance related to aging, obesity, and Type 2 diabetes. However, no studies have examined the effects of a regular exercise training program on lean, non-diabetic subjects with idiopathic insulin resistance. These 'metabolically obese normal-weight' individuals are quite common in the population and represent an important target population for exercise therapy as a prevention of the metabolic syndrome. Recently, Perseghian et al. (22) demonstrated that exercise training significantly improved muscle glucose transport in lean, insulin-resistant first degree relatives of Type 2 diabetes patients. However, it is unclear to what extent that group is representative of lean, non-diabetic, insulin resistant subjects in general.

Just as the cellular mechanisms of insulin resistance are unknown in the vast majority of cases, it is not known how chronic exercise training improves insulin effectiveness in muscle. It has been demonstrated that muscle levels of the insulin-responsive glucose transport protein (GLUT4), as well as the activity of the enzyme glycogen synthase, are elevated in athletes compared to sedentary controls. Muscle GLUT4 content has been shown to increase with exercise training in various subject groups (23). However, it is doubtful whether increases in GLUT4 can be responsible for the increased insulin action in muscle. One study failed to detect increases in insulin receptor binding or tyrosine kinase activity following training in healthy young subjects (24). Whether exercise training can be utilized to improve insulin receptor function in subjects with insulin resistance linked to impaired receptor tyrosine kinase activity has not been studied.

Inclusion/exclusion criteria (list)

Inclusion criteria:
Men and women aged 20-50
No regular exercise for past 2 years

Exclusion criteria:
Diabetes
Cardiovascular disease
Pregnant or lactating females
BMI >27
Medications that may interfere with carbohydrate metabolism - glucocorticoids, adrenergic agonists, ACE inhibitors, alpha blockers, diuretics, beta blockers, oral contraceptives, HMG CoA reductase inhibitors
History of epilepsy, cancer, hepatitis, active infection, active Graves' disease, cystic fibrosis, sickle cell anemia, peripheral vascular disease, cerebrovascular disease, asthma
Any medical condition that in the opinion of the investigator will interfere with safe completion of the trial.
Inability to give informed consent
Prior participation in a clinical trial that could potentially alter insulin sensitivity: e.g. use of new insulin sensitizers.
HIV seropositive
Anemia (Hgb < 12 g/dl) Method of contact/recruitment (be specific) Awareness for the study will be through flyers and, if necessary, local print advertising. Advertisements, letters or notices will be submitted to the CHR for review. Prospective subjects will be asked to call the Diabetes and Endocrine Research Unit to register for the study.

Benefits/burden for participants
Blood and tissue samples will be numerically coded to protect subject confidentiality. A trained phlebotomist will be responsible for drawing blood samples and assuring the comfort of the patient. The muscle biopsy procedure carries little risk beyond the possible adverse reaction to the anesthetic. Subjects will be asked about possible allergies prior to this procedure, and will be monitored carefully for adverse reactions during the procedure. The technician at the GCRC involved in this procedure has performed hundreds of muscle biopsies with little or no complications. The hyperinsulinemic euglycemic clamp carries a minimal risk. This procedure is supervised by a physician, and the only potential risks are those of establishing and maintaining indwelling catheters for several hours. The risk of hypoglycemia is minimal.

Prior to training, all individuals will undergo a physician supervised graded exercise test. Any individuals who manifest contraindications to exercise will not continue with the protocol. The exercise sessions themselves will be supervised by trained staff and are designed to be of moderate intensity, and should be well tolerated. Heart rate is monitored continuously through the session.

Any benefits or burden to DGIM practitioners?

Timeline for recruitment
Study is currently enrolling and is scheduled to stop enrollment in 2009.

Funding source
The National Institute of Health

Potential for DGIM collaborators?
Drs. Goldfine (PI), Masharani (Co-PI), and Youngren (Co-PI) welcome collaborations utilizing this cohort

Do you agree to notify us when recruitment is completed?
Yes

Date form completed
May 25, 2006

Investigators
PI: Uri Ladabaum, M.D., M.S.,
uri.ladabaum@ucsf.edu

Primary contact: Annie Sharabidze, CRC,
ann.sharabidze2@ucsf.edu

Research question

Does the selective serotonin reuptake inhibitor (SSRI) citalopram (Celexa) decrease the severity of clinical symptoms and the degree of visceral hypersensitivity compared to placebo in patients with irritable bowel syndrome?

Inclusion/exclusion criteria

Inclusion criteria:

1. Females or males with moderate IBS symptomatology, meeting Rome II criteria (abdominal pain or discomfort for at least 12 weeks of the previous 12 months, associated with two of the three following features: pain relieved with defecation, onset associated with a change in frequency of stool and onset associated with a change in form [appearance] of stool).
2. At least 18 years of age.
3. Good general health and ability to give informed consent.
4. No organic explanation for symptoms, including normal endoscopic evaluation of the colon by either colonoscopy or flexible sigmoidoscopy within 5 years of enrollment.

Exclusion criteria:

1. Individuals who are pregnant or plan to become pregnant.
2. Vulnerable populations such as prisoners, children, institutionalized individuals or persons unable to give informed consent.
3. Other treatment for IBS except fiber during the screening period and trial (prokinetics, antispasmotics, anticholinergics and other antidepressants).

Method of Contact/Recruitment

Primary care providers and gastroenterologists, in the UCSF system, will be informed about the study by fliers, e-mails, and announcements at conferences. The physicians will then be asked to identify potential subjects in their clinical practices at the time of routinely scheduled visits. The physicians will briefly introduce the study to the potential subjects in their primary care or gastroenterology clinics, simply to determine if patients grant permission to be contacted by the study investigators.

If given permission, the primary care physicians and gastroenterologists will forward the patient's name to one of the study investigators who will then contact the potential subject by telephone to provide a general description of the study. For interested subjects, a meeting with the study investigators will be arranged to discuss the study in detail. The interested individual will meet with a study investigator in the office of Dr. Ladabaum or the GCRC. At this time the study will be explained in detail. Interested subjects will then provide informed, written consent.

Benefits/burden for participants

Potential benefits of participation:

1. Insight into the origin of symptoms in IBS.
2. Compensation for time and effort.
3. Possible symptomatic benefit from treatment.

Potential risks of participation:

1. Tube placement: The risks of rectal tube placement are minimal. Similar techniques have been used extensively and safely in the past by Dr. Ladabaum and numerous other investigators. Side effects include slight anal discomfort and a very remote possibility of gastrointestinal perforation.
2. Controlled rectal distension with barostat: This technique has been performed safely by many investigators. The pressures produced by the balloon are not of sufficient magnitude to cause perforation. By the nature of the study, subjects may experience unpleasant symptoms during balloon inflation.
3. Treatment with citalopram: Citalopram is a very safe medication. The most common side effects include dry mouth, somnolence or insomnia, diarrhea and nausea. Severe mood alteration is possible but very unlikely (1% or less).
4. Inconvenience: Pills must be taken for eight weeks and time will be taken to obtain informed consent and complete sensory testing and symptom questionnaires.
5. Boredom: Boredom may be experienced during break periods between sensory tests.
6. Confidentiality: Subject social security numbers will be needed for check payment. This may increase the risk of loss of confidentiality.

Measures taken to minimize risk:

1. Subjects will be excluded for any serious underlying illness. Dr. Ladabaum or Dr. Pepin will be present for the entire sensory testing protocol.
2. Tube Placement: Dr. Ladabaum or Dr. Pepin will place the rectal tube.
3. Controlled rectal distension with barostat: The barostat contains safety features such as a button to inactivate the device and automatic shut-off for pressures or volumes exceeding a pre-set maximum. The tubing contains valves that may be manually opened to vent the equipment. In the event of possible malfunction, the barostat balloon will be immediately withdrawn from the subject. In the event of excessive symptoms, the balloon will be immediately deflated.
4. Treatment with citalopram: Subjects are instructed in the consent form to contact the investigator immediately if severe mood alterations or suicidal ideation occurs. Treatment will be stopped for any serious side effect and participation in the study will be terminated. The subject will be followed clinically until resolution of the mood alteration. In severe cases, referral to the psychiatry service may be required.
5. Inconvenience: Subjects will be compensated for their time and effort.
6. Boredom: Subjects may read, rest or sleep.
7. Confidentiality: Every effort will be made to keep subjects' participation confidential.

Any benefits or burden to DGIM practicioners?

Benefits:
1. Pariticipation in research on an important question.

Burden:
1. Minimal time commitment (study was designed with attention to the busy schedule of practicing clinicians).

Timeline for recruitment

Currently enrolling.
Anticipate enrollment for 1-2 years, depending on actual accrual rate.

Funding source

Clinical Associate Physician Award to Dr. Ladabaum.

Potential for DGIM collaborators?

Collaboration would be most welcome.

Name of project:
Reproducibility of Biochemical Markers of Bone Turnover in Clinical Practice

Investigators:
Douglas C. Bauer, MD (PI)
DBauer@psg-ucsf.org

Anne L. Schafer, MD (co-PI, primary contact)
aschafe@itsa.ucsf.edu

Negean Mahmoudi, MD (co-PI)
negean@alum.dartmouth.org

Rageshree Ramachandran, MD
Rageshree.Ramachandran@ucsf.edu

Research question:
What is the reproducibility, between clinical laboratories and for a given laboratory over time, of the markers of bone turnover urinary N-telopeptide and serum bone-specific alkaline phosphatase?

Brief background/Significance:
Recent investigation has shown that biochemical markers of bone turnover can confirm a biochemical response to treatment of osteoporosis with antiresorptive agents, and that early changes in these markers predict long-term changes in bone mineral density [1]. Although several bone turnover markers are FDA-approved, they are not frequently used in clinical practice.

One factor contributing to this low utilization is the unestablished reproducibility of the markers between laboratories and within a given laboratory over time. A study of two less commonly-utilized markers of bone turnover, urinary pyridinoline and deoxypyridinoline (DPY), used pooled specimens sent to 15 US laboratories to calculate the between-laboratory coefficient of variation (CV). The researchers found that the between-laboratory CV for DPY ranged from 9-18% for DPY measured by immunoassay, and from 22-34% for DPY measured by high performance liquid chromatographic method [2]. The researchers concluded that "there is an urgent need to improve analytic imprecision and among-laboratory variability." Subsequently, a study investigating interlaboratory variation of biochemical markers of bone turnover for European laboratories found that in identical samples, results for a given marker by identical methods differed up to 7.3-fold, with CVs ranging from 6.4-48% [3].

Our study consists of cross-sectional and longitudinal analyses of reproducibility of two biochemical markers of bone turnover: urinary N-terminal cross-linked telopeptide of type I collagen (NTX), and serum bone-specific alkaline phosphatase (BAP). We will study the cross-sectional reproducibility between clinical laboratories by submitting identical urine and serum specimens (from common urine and serum pooled specimens created from volunteers) to six laboratories for analysis of urine NTX and serum BAP. To assess the longitudinal reproducibility within each laboratory, we will submit identical specimens serially to each laboratory. The clinical laboratories examined-six high-volume US reference laboratories-will be unaware of our investigation.

We hope that the information gathered in our study will be informative both to the laboratory medicine community, and to clinicians considering whether and how to use biochemical markers of bone turnover in clinical practice.

[1] Greenspan SL et al. Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy in representative elderly women: a randomized clinical trial. J Bone Miner Res 1998; 13:1431-8.
[2] Vesper et al. Comparison study of urinary pyridinoline and deoxypyridinoline measurements in 13 US laboratories. Clinical Chemistry 2001; 47:2029-31.
[3] Seibel MJ, Lang M, Geilenkeuser WJ. Interlaboratory variation of biochemical markers of bone turnover. Clinical Chemistry 2001; 47:1443-50.

Inclusion criteria:
Postmenopausal women not taking therapy for osteoporosis

Exclusion criteria:
Use of therapy for osteoporosis

Method of contact/recruitment:
We will post advertisement flyers in public areas in and around the UCSF Medical Center in order to recruit potential study participants. Participants do not need to be UCSF patients. Women interested in participating will telephone Dr. Anne Schafer and will answer questions to confirm their eligibility. Dr. Schafer will provide each woman with an information sheet and will obtain informed consent verbally. On an agreed-upon day, the four or five participating women will undergo one-time phlebotomy and urine collection in the UCSF outpatient laboratory, using no personal identifiers while submitting those specimens but rather using pseudo-patient numbers provided by the medical center.

Benefits/burden for participants:
Benefits: There will be no direct health benefits to study partipants. However, the knowledge gained from the study will potentially benefit society by enhancing understanding of the clinical use of biochemical markers of bone turnover. Volunteers will receive a one-time payment of $30 after successful specimen collection, for reimbursement of time and travel expenses.

Burden/risks: Participants will spend approximately 30 minutes undergoing phlebotomy and urine specimen collection. Discomforts include pain associated with phlebotomy, including possible lightheadedness or bruising at the phlebotomy site. There is a very small risk of infection at phlebotomy site. Breach of confidentiality is not a risk, as all serum and urine specimens sent to the laboratories will be from pooled, anonymous samples, and no identifying information about the contributing participants will be shared outside of the research team.

Any benefits or burden to DGIM practitioners?
DGIM practitioners will benefit from the knowledge gained from the study in that they will better understand the clinical use of biochemical markers of bone turnover. Indeed, an intended strength of this study is its aim to directly impact clinical practice. There will be no burden to practitioners.

Timeline for recruitment:
February, 2006: Post advertisement flyers; field phone calls from potential participants
March, 2006: Collect serum and urine; process specimens; send specimens to laboratories
March, 2006 through July, 2006: Continue to send specimens to laboratories; receive data from laboratories
July, 2006 through November, 2006: Analyze data

Funding source:
Proctor & Gamble Pharmaceuticals has funded this study.

Potential for DGIM collaborators?
We would welcome collaboration from other physicians or from students interested in the study.

Name of Project:
Cognition in Aging and Mild Cognitive Impairment

Investigators:

Bruce Miller, MD (PI)
bmiller@memory.ucsf.edu

Julene Johnson, PhD (primary contact)
jkj@itsa.ucsf.edu

Adam Gazzaley, MD, PhD
adamgazz@comewander.com

Joel Kramer, PsyD
Kramer@itsa.ucsf.edu

Katie Freeman, Study Coordinator
KFreeman@memory.ucsf.edu

Research question(s):

We are interested in studying the effects of aging on cognition. The purpose of the research is to study the clinical outcomes of individuals who have complaints about their thinking abilities, including memory, concentration, language, or spatial abilities. To accomplish this goal, we are recruiting and following a group of individuals who have complaints about their thinking abilities.

Brief Background/Significance:

Advancing age is often accompanied by changes in cognition or thinking. Cognitive impairment without dementia in older adults is 2-5 times more common than dementia. The vast majority of studies about cognitive aging focus on memory decline and Alzheimer disease. However, the preclinical stage of Alzheimer disease and other dementias may begin with impairment in non-memory cognitive domains. Thus, there is a need to better understand what changes in cognition are risk factors for future declines in cognition or function. This project will help us better understand which changes in cognition are risk factors for future cognitive decline or functional disability.

Inclusion/exclusion criteria

Inclusions:

• Complaints about thinking abilities (e.g., memory, concentration, language, spatial)
• UCSF General Medicine patients (> 40 years of age)
• Fluent in English
• Willing to complete MRI of brain (sedation can be used)

Exclusions:

• Dementia
• Current neurological diagnosis (e.g., Parkinson's, Stroke)
• Current major psychiatric disorder
• Current alcohol or drug abuse

Method of contact/recruitment

DGIM practitioners can either 1) give a study brochure with the study coordinator's name and number to participants or 2) provide Katie Freeman with the name and phone number of the potential participant. Katie Freeman will contact the potential participant by phone and complete the Phone Screening Form. If participants qualify and are interested in participating, the first UCSF research visit will be scheduled.

Benefits/burden for participants

Potential benefits for participants (all free of charge):
1. Yearly neurological examination
2. Yearly neuropsychological examinations
3. MRI of brain
4. Parking provided

Potential burden for participants:
1. Yearly visits that may take 1-3 visits
2. Potential risk for loss of privacy
3. Neuropsychological testing may be fatiguing, but can be scheduled at the participant's convenience

Any benefits or burden to DGIM practitioners?

The DGIM practitioners will benefit from having their patients with cognitive complaints followed. With the participant's permission, we will send a letter summarizing our impressions to the DGIM practitioner. We are also available via phone for consultation.

Timeline for recruitment (projected start and stop dates)
Start Date: September 2005
Stop Date: September 2010

Funding source: NIH National Institutes on Aging

Potential for DGIM collaborators?
We invite participation from any DGIM practitioners, residents, or fellows.

Investigators.
John Conte, MD
Professor
Epidemiology & Biostatistics
jconte1@itsa.ucsf.edu

Co-Principal Investigator:
Jeff Golden, MD
Professor
Medicine

Research Objective:

The purpose of this investigation is to study the intrapulmonary pharmacokinetics/pharmacodynamics (PK/PD) of high dose levofloxacin in healthy adults and adults with chronic obstructive pulmonary disease (COPD) and to compare the PK/PD of the 750 with the 1000 mg dose. These data should be of considerable value in better understanding treatment strategies for respiratory infection.

Brief Background/Significance:

Levofloxacin is a quinolone antimicrobial that is approved for the treatment of community and hospital acquired pneumonia. It is active against gram-positive organisms such as penicillin-susceptible and penicillin-resistant S. pneumoniae, Enterococcus faecalis, methicillin susceptible Staphylococcus aureus and Staphylococcus epidermidis, and Streptococcus pyogenes. It is also active against atypical causes of respiratory infection such as C. pneumoniae, L. pneumophila, and M. pneumoniae. Levofloxacin is also active against aerobic gram-negative rods such as H. influenzae, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, Serratia marcescens and Acinetobacter baumannii 1,2 and some anaerobes. The recommended parenteral dose for community acquired pneumonia is 500 mg once-daily intravenously for 7-14 days or 750 mg once daily for 5 days; for hospital acquired pneumonia the recommended dose is 750 mg once daily for 7-14 days 4. There is recent interest in exploring an increased dose of levofloxacin to further shorten the course of either community acquired or hospital acquired pneumonia and to deter the evolution of antibiotic resistance by increasing intrapulmonary drug concentrations. 1000 mg doses of levofloxacin have been administered safely to healthy volunteers and subjects with AIDS.

Intrapulmonary drug concentrations have been studied in subjects who received a single oral 500 mg dose and who were undergoing lung biopsy or lobectomy 5. These data indicated that penetration into pulmonary tissue was appreciable and that lung tissue concentrations were 2 to 5 fold greater than corresponding plasma concentrations. Tissue concentrations of the 750 mg dose, but not the 1000 mg dose, have been studied

Inclusion/exclusion criteria:

Inclusion Criteria

• Age: 21-55 years of age in healthy volunteers and 21-65 years of age in subjects with COPD.
• Gender: men or women; women of childbearing potential must have a negative pregnancy test prior to enrollment. Contraception will be used during and for one month after the study in order to avoid the effects of systemically absorbed drug on a fetus.
• For the COPD subjects, presence of mild-moderate COPD as defined by FEV1/FVC <70%; FEV1>50% predicted * Written informed consent obtained

Exclusion Criteria

• Known hypersensitivity or intolerance to lidocaine and/or levofloxacin or any other quinolones.
• Presence of symptoms within one month prior to enrollment that are suggestive of acute respiratory infection, including productive cough, elevated body temperature (>38.5o C), shortness of breath, or chest pain.
• Use of any investigational drugs within 30 days of start of study.
• Except for COPD as defined above, presence of clinically significant cardiac, pulmonary, vascular, hepatic, gastrointestinal or renal disease.
• Smoking within the past year prior to enrollment for healthy volunteers.
• Screening laboratory values outside the range of normal for CBC, liver and renal function that are judged to be clinically significant.
• The requirement to take continuous medication for chronic illness, other than self prescribed vitamins, birth control pills, prescribed hormonal replacement or for COPD subjects-specific COPD drug therapies prescribed by a physician. * Use of alcohol and all drugs within 48 hours prior to enrollment or during the study.
• Pregnant or lactating females.

Method of contact/recruitment

Informational flyers will be distributed to pulmonary and primary care clinics through out the bay area. All interested participants may call the contact number on the flyer and have a telephone screening for eligibility. Those participants who might meet study criteria will be asked to come to UCSF for a more detailed screening evaluation and informed consent. Study investigators may send a CHR-approved letter to colleagues asking for referrals of eligible patients who might be interested in the study. Providers will also be given informational flyers to distribute to patients who might be interested in participating in the study. Benefits/burden for participants (clearly identify potential for harm) There are no direct benefits for subjects volunteering in this study but they will be reimbursed $400.00.

Any benefits or burden to DGIM practitioners? The burden to DGIM practitioners will be minimal and will only include the time spent passing out flyers to participants interested in the study. Timeline for recruitment (projected start and stop dates) After we have recruited 16 volunteers with mild to moderate COPD.

Funding source

Industry sponsored - Ortho McNeil Pharmaceuticals

Potential for DGIM collaborators?
(We encourage DGIM resident and fellow involvement in particular) We would appreciate any collaboration with providers, residents and fellows who might be interested in the study.

PI: Patricia Areán, PhD
pata@lppi.ucsf.edu

Primary Contact/Project Coordinator: Scott Mackin, PhD
scottm@lppi.ucsf.edu

Research Objective:

Evaluate the efficacy of Problem Solving Therapy (PST) and Supportive Therapy (ST) in the treatment of cognitively impaired, but non-demented, elderly patients with Major Depression, a population for which limited psychotherapy studies exist.

Brief Background/Significance:

The Over 60 Program at UCSF is conducting a 5-year NIMH-funded study to compare the efficacy of two types of individual psychotherapy. This program offers therapy to adults who are 60 years and older, stressed, feeling down, depressed or who want help coping with medical problems, physical problems or family problems. The study is looking especially for people who also may be having mild difficulties in planning, initiating and following through on daily activities, or trouble with making decisions or memory problems. These symptoms could indicate executive dysfunction. Studies have shown that executive impairment is associated with poor and unstable response to a variety of antidepressants; therefore, identifying an effective psychotherapy is critical.

The COPE-D study's free psychotherapy services are designed to compare the efficacy of Problem Solving Therapy (PST) to that of Supportive Therapy (ST) in this population. Both methods are effective in treating older adults with depression. However, this study seeks to determine which one is more effective in treating patients with major depression and executive dysfunction. This combination of symptoms (as defined in our preliminary studies) is prevalent, debilitating, and responds poorly to treatment with antidepressant agents.

Inclusion/exclusion criteria

1. Age 60 and older
2. English-speaking
3. Major Depressive Disorder
4. Mild cognitive impairment, i.e. difficulties with attention, concentrating, memory or planning

Exclusion criteria:

1. Primary Substance Abuse/Dependence
2. Psychotic Disorders
3. High suicide risk, i.e. intent or plan to attempt suicide in near future
4. Axis II diagnosis of antisocial personality (by SCID-P and DSM-IV)
5. History of head trauma with loss of consciousness, or Axis I psychotic disorders, OCD, panic disorder, bipolar disorder, hypomania and dysthymia
6. Dementia: MMSE below 24 or clinical diagnosis of dementia by DSM-IV
7. Acute or severe medical illness, i.e., delirium, metastatic cancer, decompensated cardiac, liver or kidney failure, major surgery, stroke or myocardial infarction during the three months prior to entry; or drugs known to cause depression, e.g., reserpine, alpha-methyl-dopa, steroids
8. Current involvement in individual psychotherapy
   9. Inability to perform any of the ADLs (MAI: ADL subscale) even with assistance, e.g. walking with a cane is not an exclusion criterion
9. Aphasia interfering with communication

Method of contact/recruitment
We are recruiting 120 participants to complete 12 weeks of treatment and sequential research interviews to track the course of depression. Participants are referred to the program via a primary care physician, community service agency, or self-referred from seeing flyers and ads posted in community centers and newspapers. When they call the Over 60 Program, a research associate will explain the study and services in more detail. Those participants who might meet study criteria will be asked to come to UCSF for a screening evaluation to determine whether services will be beneficial for the participant. If accepted to the study, the participant will be randomly assigned to either method of therapy and will receive 12 weeks of free psychotherapy sessions. They will also be interviewed on a weekly basis (separate from the therapy sessions) and will be given monetary compensation ($10-30 per interview). Participants who are not eligible to participate in the study will be referred to other free or affordable services in the community.

Benefits/burden for participants
The benefits to subjects are free of cost:

1. 1. Psychiatric evaluation
2. Ongoing monitoring of their clinical state
3. Treatment with one of two active psychotherapies
4. Services can be provided at preferred location to patient if needed
5. Psychiatric evaluation if needed
6. Assistance with referral if needed

Potential risks for participants:
The primary risk of participation in this study is that participants may not recover from their depression. While both interventions are found to be efficacious in treating Major Depression in older adults, they have yet to be tested for older adults with Major Depression and executive dysfunction. Therapists closely monitor participants, and if one becomes significantly more depressed (i.e. symptoms of depression become worse), they will be offered alternative treatment through Langley Porter Psychiatric Institute.

Benefits/burden for DGIM practitioners
This project provides a referral option for the treatment of older, depressed patients, regardless of patients' insurance, financial means or location in San Francisco. DGIM practitioners need only provide the Over 60 Program phone number (415-476-7439) or obtain the patient's expressed consent to be contacted about this study.

Timeline for recruitment (projected start and stop dates)
Participant recruitment, intervention delivery and data collection began in April 2003. Participants will be enrolled in the study for a total of 36 weeks. We will continue to enroll participants until December 2007. We anticipate no more than a two-week lag between treatment termination and post-treatment evaluation.

Funding source National Institute of Mental Health (NIMH) was awarded 10/1/2002.

Investigator: Principal Investigator and Primary Contact:
Celia Kaplan, DrPH, MA
ckaplan@itsa.ucsf.edu

Research question

The overall goal of this proposal is to increase awareness of and participation in clinical and behavioral research among patients from UCSF. We propose to develop a patient education brochure in English and Spanish highlighting UCSF's research activities and the ways in which this research benefits the larger UCSF community. Focus groups will be conducted among English- and Spanish-speaking UCSF patients to assess factors that facilitate or hinder participation in and the acceptance of research. Based on input from the focus groups, a preliminary brochure will be developed and pilot tested through qualitative interviews with English- and Spanish-speaking patients. The finalized brochure will be distributed to UCSF patients and a final evaluation of its effectiveness will be conducted through interviews with a subset of these patients.

Brief Background/Significance:

In spite of UCSF's mission to produce a steady stream of scientific knowledge and clinical achievements and to make such knowledge available through education and technology transfer, rates of research participation among UCSF patients remain suboptimal. Data derived from the San Francisco Mammography Registry, for example, show that only 54% of UCSF women receiving a mammogram agreed to be contacted for future research. Minority women agreed to participate at even lower rates than non-Latina whites, which is especially troubling given the historical under-representation of minorities in clinical research. One possible reason for the low levels of interest is a lack of information about the contributions of UCSF to research. The Cancer Center Minority Task Force has therefore identified the dissemination of information as an important area to address. This proposal attempts to improve recruitment by providing information to patients about the value of the research conducted at UCSF, the individuals conducting the research, other patients' experiences participating, and the ethical considerations of conducting research.

Inclusion/exclusion criteria

Inclusion: UCSF patients recruited through Mt. Zion's general internal medicine clinic or cancer clinic, ages 18 or older, who speak English or Spanish. Exclusion: Individuals will be excluded if they are not patients of Mt. Zion's general internal medicine or cancer clinics, if they are under the age of 18, or if they are non-English- or Spanish-speaking.

Method of contact/recruitment

Informational fliers will be distributed throughout Mt. Zion's general internal medicine and cancer clinics and all interested patients may call to be screened for eligibility. Bilingual trained interviewers will determine eligibility based on the criteria described previously. Current contact information for all eligible patients will also be obtained via telephone, and letters, consent forms, and information sheets in the preferred language will then be mailed. Two weeks after the initial mailing, all participants will receive a follow-up telephone call to schedule the focus group, qualitative interview or evaluation survey.

To ensure optimal recruitment of participants for the focus groups and qualitative survey, we will also obtain a list of potential participants in the following way: Physicians from the Division of General Internal Medicine have agreed to identify eligible patients through their practice based on our criteria described previously. Once the list of patients has been provided by the physicians with permission to contact them, addresses and phone numbers will be retrieved through the STOR system by Division of General Internal Medicine administrative analyst, Tirzah Gonzalez. An invitation letter, a participant information sheet, and a pre-addressed, postage-paid refusal postcard will then be sent to all potential participants. Two weeks after the initial mailing, all participants who have not sent refusal postcard will receive a telephone call following up on the letter to assess interest in scheduling either the focus group or qualitative survey. If the patient is interested in participating at that point, the focus group or qualitative interview will then be scheduled.

Benefits/burden for participants

There are no physical risks associated with any of the interviews. Potential risks/discomforts are minimal and include the possible loss of privacy and psychological anxiety associated with discussion of barriers to and acceptance of participation in research. The study will provide an opportunity for UCSF patients to learn about the research being conducted within the institution and may lead to participation in potentially life-saving treatment protocols.

Any benefits or burden to DGIM practitioners?

The burden to DGIM practitioners will be minimal and will include providing a list of eligible participants. The development of the brochure will lead to an increased understanding of and participation in medical research, and may be used as a tool for future recruitment of minorities to participate in research

Timeline for recruitment (projected start and stop dates) Projected start date: January, 2005 Projected stop date: June, 2005

Name of Project:
The Influence of Social Networks on Drinking Behavior

Investigators:

PI: Dr. Peter Nygaard
Email: pnygaard@prev.org

Primary Contact: Dr. Mark Pletcher
Email: mpletcher@epi.ucsf.edu

Dr. Jason Satterfield
Email: jsatter@medicine.ucsf.edu

Inclusion/exclusion criteria:

Inclusion: Living patients, 25-60 years old, who have visited one of the three general medicine practices (GMA, GMB or GMZ) within the last year.

Search criteria: ICD-9 codes for alcohol abuse; ICD-9 codes for alcohol dependence; alcoholism, alcohol binges, alcohol treatment, alcohol poisoning, alcohol issues, alcohol withdrawal, alcohol abuse, alcohol dependence, alcohol cirrhosis, alcohol gastritis, recovered alcoholic, alcoholic liver disease, alcohol inpatient.

Exclusion: Abstainers, Non-English speakers.

Cases: Problem drinkers (confirmed by phone interview)

Controls: Social drinkers (confirmed by phone interview), matched on age, gender, ethnicity and primary language

Timeline for recruitment:
Start: Fall 04
End: Winter 05

Investigators:
Kathryn Phillips, PhD; UCSF School of Pharmacy - kathryn@itsa.ucsf.edu
Judith Walsh, MD, MPH; UCSF DGIM - jmwalsh@itsa.ucsf.edu
Deborah Marshall, PhD (McMaster Univertsity
John Marshall MD (McMaster University)
Lehana Thabane PhD (McMaster University)

Background:

Although colorectal cancer screening tests are currently recommended for all individuals aged 50 and over, current rates of screening remain low. CRC screening is more complicated than other screening because a variety of screening tests are offered and patients and physicians must make trade offs among strategies with respect to accuracy, expected health gains, frequency, discomfort risk and costs.

In order to better understand patient and physician preferences about various aspects of CRC screening, we propose administering a survey to three sample populations: 1) patients attending DGIM clinics, 2) primary care providers and 3) a Web based sample of patients and physicians (Harris Poll online)

Patient sample: In accordance with HIPAA recommendations, we will ask DGIM providers for permission to contact individual patients by letter. For those whom provider consent is received, a letter will be sent from Dr. Phillips (attached Study Information Sheet to UCSF Patient Population) describing the study to potential participants,. Participants can then send in a refusal post card or can complete the enclosed survey and return it in the enclosed envelope. Participants who complete the survey are assumed to have given implied consent. All who complete the survey will receive a $1 gift certificate

Inclusion/Exclusion criteria:

Patients who are aged 45-70 and have been seen in one of the UCSF General Internal Medicine Clinics in the past year will be eligible for inclusion.

All UCSF DGIM Providers (attendings and residents will be eligible for participation).

Timeline for Recruitment:

Providers will review patient lists beginning as soon as approval has been received for this study and after the relevant patient names are selected from the STOR database and sorted by provider. We hope to have a completed patient contact database by the end of December 2004.

Patients will be mailed surveys in January 2005. Patients who have not responded within two weeks of the initial mailing will receive reminder postcards (mid-late January 2004). Patients who still do not return the survey within 30 days will be sent a second copy of the survey and associated information as well as additional consent forms (end January - beginning February 2005). There will be no further contact with patients following the second mailing.

Providers will also be mailed surveys in January (via intercampus mail). Follow-up with providers will be conducted via phone and email as required.

Common Colds in Asthmatic and Non-Asthmatic Subjects: Predictors of Asthma Exacerbations

1.Do rhinoviruses that cause simple head cold symptoms differ from rhinoviruses that cause head cold symptoms and lower airway symptoms (cough, phlegm, chest tightness, dyspnea, wheezing or chest pain during a cold)?

2.Do inflammatory markers in nasal lavage or sputum samples differ between subjects with simple head colds and those with head colds and lower airway symptoms?

3.Can DNA microarray be used to detect viruses in nasal lavage or sputum samples?

Approved: Winter 04

PI: Homer Boushey, MD hab2@itsa.ucsf.edu
Co-PI: Pedro Avila, MD avila@itsa.ucsf.edu
Contact: Theresa Ward, RN wardt@itsa.ucsf.edu

Investigator(s):
John A. Shepherd, PI
john.shepherd@radiology.ucsf.edu

Karla Kerlikowske, Co-PI
kerliko@itsa.ucsf.edu

Jessie Landau, Study Coordinator (primary contact)
jessie.landau@radiology.ucsf.edu

Research question(s):

• To further develop and validate a method to measure tissue composition using single x-ray absorptiometry (SXA) techniques using standard mammogram x-ray protocols against known standards of compositional density (DXA and phantoms).
• To develop and characterize a new method of measuring breast tissue composition using bioimpedance analysis (BIA). The method is designed to measure breast density as percentage fat at the time of standard film screen mammography without user intervention or the viewing of an image.
• To quantify the precision of the bioimpedance technique in vivo.
• To gather preliminary data to determine whether women with a greater proportion of compositionally dense breast tissue are at greater risk of breast cancer than women with less compositionally dense breasts controlling for known risk factors.
• To determine the correlation between breast compositional density methods and mammographic density.
• To quantify the repeatability in measuring breast tissue composition using either the SXA, DXA, bioimpedance, or the more conventional mammographic density methodology.

Brief Background/Significance:
Mammographic breast density is one of the strongest predictors of breast cancer risk. Women with greater than 50% of total breast area that is mammographically dense are at 3 to 5 fold greater risk of breast cancer than women with less than 25% mammographically dense breasts. The prevalence of mammographically dense breasts is high among breast cancer cases with 42% of cases with 50% or more mammographically dense breasts compared with 32% of those without breast cancer (OR= 3.1).

Mammographic density is quantified as a continuous grading from 0 t 100% density and defined by delineating the radiographically dense areas in the mammogram from the entire breast area and providing a percentage breast density (PD) defined as PD = (high radiographic density area)/(total breast area). Although this method has shown to be a strong risk factor, it is neither precise nor accurate enough to be used to monitor the risk of individual women.

As an alternative, we propose to measure the breast tissue on a pixel-by-pixel basis and report a percentage fat and dense mass. An SXA reference phantom has been designed for this project. The phantom provides a measure of tissue composition at the two extremes of the tissue composition scale. The phantom is placed on the upper edge of the mammogram field such that it does not interfere with the projection of the breast tissue. It is constructed of two polymers that is necessary for the measurement. Dr. Edward Sickles, MD, Chief of Breast Imaging at UCSF has agreed to allow the use of the phantom on mammography units when obtaining standard clinical films.

We will also measure breast density by taking low radiation x-ray scans of breasts on a device called a dual x-ray absorptiometer (DXA). Dual Energy X-ray Absorptiometry (DXA) body composition measurements are the gold standard for whole body and subregional compositional measurements. The final method we will use to measure breast compositional den