Kaiser Permanente Hayward Medical Center

There is continued concern about protease inhibitors (PIs) causing increased risk of coronary heart disease (CHD) in HIV-infected patients. This ongoing observational study examines CHD and myocardial infarction (MI) hospitalization rates among HIV-positive members of the Kaiser Permanente Medical Care Program of Northern California, before and after PI use, and before and after any antiretroviral therapy (ART). Also, CHD and MI hospitalization rates among HIV-infected members are compared with members not known to be HIV-positive. With 4.1 years' median total follow-up, age-adjusted CHD and MI hospitalization rates were not significantly different before versus after PIs (6.2 vs. 6.7 events per 1000 person-years); or before versus after ART (5.7 vs. 6.8). However, comparing HIV-positive and -negative members, the CHD hospitalization rate was significantly higher (6.5 vs. 3.8, p =.003), and the difference in the MI rate also was higher (4.3 vs. 2.9, p =.07). Differences between HIV-positive and -negative members in the CHD risk factors measured were mixed, and the overall clinical significance of these differences is uncertain. Our data suggest that PIs and other antiretroviral therapies do not yet increase CHD or MI hospitalizations among HIV-infected individuals; however, longer follow-up is needed. Other HIV-related mechanisms may be at work, causing increased CHD and MI risk among all HIV-infected persons.

OBJECTIVE: To evaluate the risk of cancers with and without a known infectious cause in HIV-infected persons. DESIGN: Retrospective cohort study. METHODS: Adult HIV-infected and matched HIV-uninfected members of Kaiser Permanente followed between 1996 and 2007 for incident AIDS-defining cancers (ADCs), infection-related non-AIDS-defining cancers (NADCs; anal squamous cell, vagina/vulva, Hodgkin's lymphoma, penis, liver, human papillomavirus-related oral cavity/pharynx, stomach) and infection-unrelated NADC (all other NADCs). RESULTS: We identified 20 277 HIV-infected and 202 313 HIV-uninfected persons. HIV-infected persons experienced 552 ADC, 221 infection-related NADC, and 388 infection-unrelated NADC. HIV-uninfected persons experienced 179 ADC, 284 infection-related NADC, and 3418 infection-unrelated NADC. The rate ratio comparing HIV-infected and HIV-uninfected persons for ADC was 37.7 [95% confidence interval (CI): 31.7-44.8], with decreases in the rate ratio over time (P < 0.001). The rate ratio for infection-related NADC was 9.2 (95% CI: 7.7-11.1), also with decreases in the rate ratio over time (P < 0.001). These results were largely influenced by anal squamous cell cancer and Hodgkin's lymphoma. The rate ratio for infection-unrelated NADC was 1.3 (95% CI: 1.2-1.4), with no change in the rate ratio over time (P = 0.44). Among infection-unrelated NADCs, other anal, skin, other head and neck, and lung cancer rates were higher and prostate cancer rates lower in HIV-infected persons. Among all infection-unrelated NADCs, the rate ratio decreased over time only for lung cancer (P = 0.007). CONCLUSION: In comparison with those without HIV infection, HIV-infected persons are at particular risk for cancers with a known infectious cause, although the higher risk has decreased in the antiretroviral therapy era. Cancers without a known infectious cause are modestly increased in HIV-infected persons compared with HIV-uninfected persons.

OBJECTIVE: To assess whether, in children, oral magnesium oxide reduces migrainous headache frequency, severity, and associated features compared to placebo. BACKGROUND: There is no single, safe, widely well-tolerated, and effective prophylactic treatment for all children and adolescents with frequent migrainous headache. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group trial. METHODS: This study was conducted between June 1997 and January 2000 using 7 selected Northern California Kaiser Permanente sites. We recruited children of ages 3 to 17 years who reported a 4-week history of at least weekly, moderate-to-severe headache with a throbbing or pulsatile quality, associated anorexia/nausea, vomiting, photophobia, sonophobia, or relief with sleep, but no fever or evidence of infection. Subjects were randomly assigned to receive either magnesium oxide (9 mg/kg per day by mouth divided 3 times a day with food) (n = 58) or matching placebo (n = 60) for 16 weeks. The number of headache days (days with at least one headache) during each of eight 2-week intervals was chosen to be the primary outcome variable. RESULTS: Of those enrolled, 86 (73%) completed the study (42 received magnesium oxide and 44 placebo); 74 of 192 eligible subjects declined to participate. Baseline information on demographic factors, health status, and headache history was similar comparing the 2 groups. By intention-to-treat analysis, we found a statistically significant decrease over time in headache frequency in the magnesium oxide group (P =.0037) but not in the placebo group (P =.086), although the slopes of these 2 lines were not statistically significantly different from each other (P =.88). The group treated with magnesium oxide had significantly lower headache severity (P =.0029) relative to the placebo group. CONCLUSIONS: This study does not unequivocally determine whether oral magnesium oxide is or is not superior to placebo in preventing frequent migrainous headache in children, but treatment with the active agent did lead to a significant reduction in headache days. Larger trials involving this safe, appealing complementary therapy are needed.

Early detection of HIV infection improves prognosis and reduces transmission, but 30%-40% of cases are diagnosed late. A comprehensive and systematic review of medical encounters before diagnosis has not been done. This study reviews 5 years of medical encounters before the diagnosis of HIV infection in members of a large managed care organization where access to care is reasonably good. Patient characteristics, HIV risk factors, and clinical events preceding diagnosis were examined and tested for association with late diagnosis (CD4 cell count of <200/microL at diagnosis). Of 440 HIV-infected patients, 62% had CD4 cell counts of <350/microL, 43% had CD4 cell counts of <200/microL, and 18% had CD4 cell counts of <50/microL at diagnosis. Twenty-six percent of all patients had risks documented >1 year before diagnosis. Only 22% of patients had one of eight clinical indicators suggested in the literature as reasons to test for HIV >1 year before diagnosis. In multiple logistic regression, older age, male sex, race, risk group, no prior HIV testing, physician-initiated testing, and having any of eight clinical indicators before diagnosis were each associated with late diagnosis (p <or=.05). Late diagnosis remains a challenge despite good access to care. In our setting, effective risk assessment before symptoms arise offers greater potential for raising the mean CD4 cell count at diagnosis than does increased awareness of selected HIV-associated clinical prompts.

Endostatin and angiostatin are known as tumor-derived angiogenesis inhibitors, but their mechanisms of action are not yet completely defined. We report here that endostatin and angiostatin, delivered by adenoviral vectors, reduced in vitro the neovessel formation in the mouse aortic ring assay by 85 and 40%, respectively. We also demonstrated in vivo that both endostatin and angiostatin inhibited local invasion and tumor vascularization of transplanted murine malignant keratinocytes, and reduced by 50 and 90% the development of highly vascularized murine mammary tumors. This inhibition of tumor growth was associated with a reduction of tumor vascularization. Expression analysis of vascular endothelial growth factor (VEGF) carried out in the mouse aortic ring model revealed a 3- to 10-fold down-regulation of VEGF mRNA expression in endostatin-treated rings. A similar down-regulation of VEGF expression at both mRNA and protein levels was also observed in the two in vivo cancer models after treatment with each angiogenesis inhibitor. This suggests that endostatin and angiostatin effects may be mediated, at least in part, by their ability to down-regulate VEGF expression within the tumor. This work provides evidence that endostatin and angiostatin act on tumor cells themselves.

Foreword. 1. When the First Session Is the Only Session. 2. The First Phone Call: Presession Screening and Preparation. 3. Effective Single-Session Therapy: Step-by-Step Guidelines(in collaboration with Michael F. Hoyt and Robert Rosenbaum). 4. Empowering Your Patient. 5. Single-Session Therapy in Action: A Case Example(in collaboration with Michael F. Hoyt). 6. Learning from Failures. 7. Attitudes That Facilitate Single-Session Therapy. Resources A: Follow-Up Interview. Resources B: Tips for Managing Time and Money.

BACKGROUND: A new pulmonary drug delivery system produces aerosols from disposable packets of medication. This study compared the pharmacokinetics and pharmacodynamics of morphine delivered by an AERx prototype with intravenous morphine. METHODS: Fifteen healthy volunteers were enrolled. Two subjects were administered four inhalations of 2.2 mg morphine each at 1-min intervals or 4.4 mg over 3 min by intravenous infusion. Thirteen subjects were given twice the above doses, i.e., eight inhalations or 8.8 mg intravenously over 7 min. Arterial blood sampling was performed every minute during administration and at 2, 5, 7, 10, 15, 20, 45, 60, 90, 120, 150, 180, and 240 min after administration. The effect of morphine was assessed by measuring pupil diameter and ventilatory response to a hypercapnic challenge. Pharmacokinetic and pharmacodynamic analyses were performed simultaneously using mixed-effect models. RESULTS: The pharmacokinetic data after intravenous administration were described by a three-exponent decay model preceded by a lag time. The pharmacokinetic model for administration by inhalation consisted of the three-exponent intravenous pharmacokinetic model preceded by a two-exponent absorption model. The authors found that, with administration by inhalation, the total bioavailability was 59%, of which 43% was absorbed almost instantaneously and 57% was absorbed with a half-life of 18 min. The median times to the half-maximal miotic effects of morphine were 10 and 5.5 min after inhalation and intravenous administration, respectively (P < 0.01). The pharmacodynamic parameter ke0 was approximately 0.003 min-1. CONCLUSIONS: The onset and duration of the effects of morphine are similar after intravenous administration or inhalation via this new pulmonary drug delivery system. Morphine bioavailability after such administration is 59% of the dose loaded into the dosage form.

Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy and environmental nuclear contamination as well as for Earth-orbit and space missions. Analyses of transcriptome profiles of mouse brain tissue after whole-body irradiation showed that low-dose exposures (10 cGy) induced genes not affected by high-dose radiation (2 Gy) and that low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues and pathways that were specific for brain tissue. Low-dose genes clustered into a saturated network (P < 10(-53)) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified nine neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose irradiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down-regulated in normal human aging and Alzheimer's disease.

OBJECTIVE: To examine the association between demographic and clinical features in early Parkinson disease (PD) and length of survival in a multiethnic population. DESIGN: Clinical features within 2 years of diagnosis were determined for an inception cohort established during 1994-1995. Vital status was determined through December 31, 2005. Predictor variables included age at diagnosis, sex, race/ethnicity, as well as clinical subtype (modified tremor dominant, postural instability gait difficulty), symmetry, cognitive impairment, depression, dysphagia, and hallucinations. Cox proportional hazards regression analysis was used to identify factors associated with shorter survival. SETTING: Kaiser Permanente Medical Care Program, northern California. PATIENTS: Five hundred seventy-three men and women with newly diagnosed PD. RESULTS: Three hundred fifty-two participants in the PD cohort (61.4%) had died in the follow-up period. Older age at diagnosis (hazard ratio [HR], 1.1; 95% confidence interval [CI], 1.09-1.12), modified postural instability gait difficulty subtype (HR, 1.8; 95% CI, 1.3-2.7), symmetry of motor signs (HR, 2.0; 95% CI, 1.1-3.7), mild (HR, 1.7; 95% CI, 1.3-2.2) and severe (HR, 2.7; 95% CI, 1.9-3.9) cognitive impairment, dysphagia (HR, 1.4; 95% CI, 1.1-1.9), and hallucinations (HR, 2.1; 95% CI, 1.3-3.2) were associated with increased all-cause mortality, after adjusting for age, sex, and race/ethnicity. None of the other factors altered mortality risk. In an empirical predictive analysis, most previous significant predictors remained associated with shorter survival. CONCLUSIONS: Both motor and nonmotor features in early PD predict increased mortality risk, particularly postural instability gait difficulty, cognitive impairment, and hallucinations. These predictors may be useful in clinical practice and when designing clinical trials.

Automated Multiphasic Screening and Diagnosis Morris F. Collen, DirectorB.E.E.M.D., Leonard Rubin, ChiefM.D.Ph.D., Jerzy Neyman, Professor of Statistics, DirectorPh.D., George B. Dantzig, ChairmanPh.D., Robert M. Baer, ConsultantPh.D., and A. B. Siegelaub, BiostatisticianM.S. CopyRight https://doi.org/10.2105/AJPH.54.5.741 Published Online: August 29, 2011

OBJECTIVES: We investigated the efficacy of intravitreal tissue plasminogen activator (tPA) for the treatment of acute central retinal vein occlusion. DESIGN: Twenty-six eyes with central retinal vein occlusion (CRVO, n=23) and hemi-retinal vein occlusion (n=3) with recent onset of visual symptoms (< or = 21 days) were identified and given an intravitreal injection of 65 -110 microg of tPA. RESULTS: Among eyes with CRVO, visual acuity improved to > or = 20/40 in 7 of 23 patients (30.4%) at 6 weeks, and 8 of 23 patients (34.8%) at 6 months. Visual acuity improved or stabilized in 69.6% (16 of 23 patients) at the 6 week visit and persisted with longer follow-up. Four patients developed doubling of the visual angle. No patients developed rhegmatogenous retinal detachment, infection or neovascular glaucoma. One patient developed a small vitreous hemorrhage and 2 developed an increase in the size of pre-existing macular hemorrhage. CONCLUSION: Intravitreal tPA administered early in the course of central retinal vein occlusion did not lead to catastrophic hemorrhagic events. Intravitreal tPA may cause worsening of vision in some patients. While some eyes appear to have benefited from the therapy, no conclusions can be reached because there was not a concurrent control group. A randomized clinical trial is necessary to determine its efficacy. SUMMARY STATEMENT: Intravitreal tPA administered early in the course of central retinal vein occlusion did not lead to catastrophic hemorrhagic events. A randomized clinical trial is necessary to determine its efficacy.

Many conditions in clinical neurology may be responsive to pyridoxine as a therapeutic agent. The current difficulty is in trying to isolate the conditions that are most likely to respond. Treating seizures is a major part of a neurologic practice. Our current therapeutic agents are only partially successful and limited by multiple side effects. One problem is that patients often have to take these agents for an entire lifetime, further raising the risk of toxicity. If pyridoxine supplementation can improve the efficacy of currently used medications, it will be gladly accepted into our therapeutic arsenal. Headache, chronic pain, and depression all appear to run together in many of our patients. The observations that serotonin deficiency is a common thread between them and that pyridoxine can raise serotonin levels open a wide range of therapeutic options. Small studies have been carried out with mixed success. Comparison with amitriptyline in the treatment of headache appears to show about equal efficacy, although side effects would be expected to be more of a problem with the amitriptyline. Behavioral disorders are relatively common and continue to be a major problem, disrupting the lives of the patients and their families. Current treatments are not acceptable to most people because of the risk of side effects with long-term usage. If, as Dr. Feingold suggests, many of these problems are caused by "toxic" exposures to chemicals that are pyridoxine antagonists, supplementation at early ages may reduce the incidence of hyperactivity and aggressive behavior. This raises the question of safety. Is pyridoxine safe for long-term use in large segments of the population, including children? The studies on children with Down's syndrome and autism, utilizing much higher doses than are used for other therapeutic purposes, seem to indicate relative safety if carefully monitored. Studies involving large population groups with carpal tunnel syndrome, all adults, using 100-150 mg/day have shown minimal or no toxicity in five- to 10-year studies. Women self-medicating for PMS taking 500 to 5000 mg/day have shown peripheral neuropathy within one to three years. It would appear from this retrospective analysis that pyridoxine is safe at doses of 100 mg/day or less in adults. In children there is not enough data to make any sort of suggestion. Because the major neurologic complication is a peripheral neuropathy and the causes of this condition are myriad, pyridoxine may cause neuropathy only in patients with a pre-existing susceptibility to this condition.

To investigate the autonomic components of the pupillary light reflex in humans, we used infrared pupillometry combined with a partial local cholinergic (tropicamide) or alpha-adrenergic (thymoxamine) blockade. The pupillary response curve was analyzed using parameters identical or similar to those employed previously to study the autonomic components of the pupillary light reflex. Tropicamide increased baseline pupil area and affected five of the eight measured parameters. Thymoxamine lowered baseline pupil area but did not affect any of the parameters. We found the expected cholinergic contribution to the constrictive phase of the pupillary light reflex but no evidence for peripheral alpha-adrenergic activity during redilation. We propose that redilation primarily involves parasympathetic relaxation, modulated by cholinergic inhibition of the dilator muscle and central sympathetic inhibition of the Edinger-Westphal nucleus.

"Bronchial Hyperreactivity In Chronic Obstructive Bronchitis." American Review of Respiratory Disease, 127(4), pp. 526–527

Interest in manual therapy appears to continue to grow among physical therapy clinicians and educators throughout the world even though the underlying concepts and techniques have not been justified by a knowledge base. The purposes of this article are to critically assess the role of manual therapy within the physical therapy profession and to provide an introduction to the other articles in this special issue. Eisner's model of explicit, implicit, and null curricula is used as a framework for our analysis and our discussion of manual therapy. The explicit area of manual therapy includes discussions of the definition and the role of manual therapy, the scientific rationale for manual therapy, and manual therapy in education and a comparison of manual therapy evaluative frameworks. The implicit area deals with the role of clinical decision making and critical thinking in manual therapy in education and rehabilitation. In the null (unaddressed) area of manual therapy, we suggest directions for future development and research.

While loss-of-function mutations in Gsalpha are invariably associated with the short stature and brachydactyly of Albright hereditary osteodystrophy (AHO), the association with hormone resistance (to parathyroid hormone and thyrotropin) typical of pseudohypoparathyroidism type Ia (PHP-Ia) is much more variable. Observational studies and DNA polymorphism analysis suggest that maternal transmission of the Gsalpha mutation may be required for full expression of clinical hormone resistance. To test this hypothesis, we studied transmission of a frameshift mutation in Gsalpha through three generations of a pedigree affected by AHO and PHP-Ia. While all family members carrying this loss-of-function mutation in one Gsalpha allele had AHO, neither the presence of the mutation nor the degree of reduction of erythrocyte Gsalpha bioactivity allowed prediction of phenotype (AHO alone versus AHO and PHP-Ia). Paternal transmission of the mutation (from the patriarch of the first generation to three members of the second generation) was not associated with concurrent PHP-Ia, but maternal transmission (from two women in the second generation to four children in the third generation) was invariably associated with PHP-Ia. No expansion of an upstream short CCG nucleotide repeat region was detected, nor was there evidence of uniparental disomy by polymorphism analysis. This report, the first to document the effects across three generations of both paternal and maternal transmission of a specific Gsalpha mutation, strongly supports the hypothesis that a maternal factor determines full expression of Gsalpha dysfunction as PHP-Ia.

Deregulation of apoptosis is a common occurrence in cancer, for which emerging oncology therapeutic agents designed to engage this pathway are undergoing clinical trials. With the aim of uncovering strategies to activate apoptosis in cancer cells, we used a pooled shRNA screen to interrogate death receptor signaling. This screening approach identified 16 genes that modulate the sensitivity to ligand induced apoptosis, with several genes exhibiting frequent overexpression and/or copy number gain in cancer. Interestingly, two of the top hits, EDD1 and GRHL2, are found 50 kb apart on chromosome 8q22, a region that is frequently amplified in many cancers. By using a series of silencing and overexpression studies, we show that EDD1 and GRHL2 suppress death-receptor expression, and that EDD1 expression is elevated in breast, pancreas, and lung cancer cell lines resistant to death receptor-mediated apoptosis. Supporting the relevance of EDD1 and GRHL2 as therapeutic candidates to engage apoptosis in cancer cells, silencing the expression of either gene sensitizes 8q22-amplified breast cancer cell lines to death receptor induced apoptosis. Our findings highlight a mechanism by which cancer cells may evade apoptosis, and therefore provide insight in the search for new targets and functional biomarkers for this pathway.

Peritoneal dialysis (PD) catheters can be placed by interventional radiologists, an approach that might offer scheduling efficiencies, cost-effectiveness, and a minimally invasive procedure. In the United States, changes in the dialysis reimbursement structure by the Centers for Medicare and Medicaid Services are expected to result in the increased use of PD, a less costly dialysis modality that offers patients the opportunity to receive dialysis in the home setting and to have more independence for travel and work schedules, and that preserves vascular access for future dialysis options. Placement of PD catheters by interventional radiologists might therefore be increasingly requested by nephrology practices, given that recent publications have demonstrated the favorable impact on PD practices of an interventional radiology PD placement capability. Earlier reports of interventional radiology PD catheter placement came from single-center practices with smaller reported experiences. The need for a larger consensus document that attempts to establish best demonstrated practices for radiologists is evident. The radiologists submitting this consensus document represent a combined experience of more than 1000 PD catheter placements. The authors submit these consensus-proposed best demonstrated practices for placement of PD catheters by interventional radiologists under ultrasonographic and fluoroscopic guidance. This technique might allow for expeditious placement of permanent PD catheters in late-referred patients with end-stage renal disease, thus facilitating urgent-start PD and avoiding the need for temporary vascular access catheters.

There is a need for a measure of prediction accuracy that generalizes non-parametric receiver operating characteristic (ROC) area to polytomous ordinal patient state. We describe such a measure, prediction probability PK derived from Kim's measure of association. We show that the value of PK equals the value of non-parametric ROC area for dichotomous patient state and is a meaningful generalization of non-parametric ROC area for polytomous state.

Somatic inhibitory seizures are thought to occur rarely. We describe a patient with somatic inhibitory seizures who initially presented with a clinical picture of crescendo transient ischemic attacks. He did not improve with anticoagulation, but the episodes ceased promptly after the administration of an anticonvulsant.