Wielding the implement of law: Distilling new rights and responsibilities in the age of the ‘new genetics’

The law has, to date, been slow to respond to advances in genetics, but in many ways this may be propitious. History teaches us that there is an ever-present risk that the law will be used merely to embody knee-jerk reactions to new developments in medicine and science, frequently to the detriment of all interested parties. Adequate and appropriate legal responses to genetic research can only come once a full debate on the problems to be addressed has taken place, and when society as a whole is appraised of the options at hand. This article offers an overview of the problems which are thrown up for the law by 'new genetics', including the problem of reconciling competing claims to genetic information from family members, insurers and employers, as well as the dilemma of determining how to regulate the potential range of uses of new genetic knowledge. The article offers some views on how we might use the law to proceed sensibly and productively in the future.     

Responses of movement-sensitive visual interneurons to prey-like stimuli in the praying mantis Sphodromantis lineola (Burmeister)

Previous behavioral work using both mechanical and computer-generated visual stimuli has demonstrated that mantids use a computational algorithm to recognize prey similar to that used by some amphibian predators: A stimulus elicits prey capture behavior if it falls within a perceptual envelope defined by five fundamental stimulus parameters: (1) overall size, (2) length of the leading edge, (3) contrast to the background, (4) location in the visual field, and (5) apparent speed. In this study, we recorded simultaneously from both cervical nerve cords of monocular Sphodromantis lineola while they viewed the same visual stimuli successfully used in the behavioral studies. Extracellular recordings showed three consistently proportioned amplitude classes of movement-elicited spikes in each cord and these were repeatedly and reliably identifiable across mantids. Overall, the movement-elicited activity in both cords was dominated by very large spikes suggesting the existence of several large, descending movement-sensitive interneurons projecting both ipsilaterally and contralaterally from the optic lobes. However, only the largest contralateral spikes occurred preferentially to prey-like stimuli, mirrored the behavioral response curves generated by S. lineola to the same visual stimuli, and displayed activity peaks that were correlated with the times at which the mantid emitted predatory strikes. Copyright (R) 2000 S.Karger AG, Basel     

Dual diagnosis: A treatment model for substance abuse and major mental illness

The treatment of dual diagnosis, co-occurring substance abuse and mental illness, calls for addressing two serious and often confounding problems. The authors introduce an expanded version of the transtheoretical model of change as formulated by J.O. Prochaska and C.C. DiClemente, and suggest that this new version offers a pragmatic approach to the conceptualization and treatment of dual diagnosis. The potential utility of the treatment model is presented through the authors' experiences in working with inner-city, chronic mentally ill individuals with substance abuse problems. Practical guidelines for dual diagnosis group therapy are discussed.Dr. Brady is an assistant research professor at the Boston University School of Medicine and the deputy superintendent for research and training at the Dr. Solomon Carter Fuller Mental Health Center. Drs. Hiam, Saemann, Humbert, Fleming and Brickhouse were senior members of the clinical/administrative staff at the Fuller MHC.     

Abnormal serum factors in Guillain-Barré syndrome

The Guillain-Barré Syndrome (GBS) is generally considered to be a cell-mediated immunopathologic disease of the peripheral nervous system (PNS), although the evidence for this is indirect. Both in vitro and in vivo studies of sera from experimental animals with autoimmune demyelinating neuropathies suggest that serum factors, including antibodies to PNS myelin and/or Schwann cells, may be important in the pathogenesis of some of these disorders. More recently, similar in vitro and in vivo techniques, including the production of demyelination following intraneural injection in the rat have been employed to study sera from patients with GBS. The results of these studies demonstrate the presence of factor(s), as yet not fully characterized, that may be important in mediating demyelination. Moreover, in some patients with chronic or relapsing demyelinative inflammatory neuropathies and monoclonal gammopathy, there is evidence of antimyelin antibodies to PNS myelin. Further studies of serum from patients with acute GBS and these other neuropathies may clarify the role of serum factors in acquired inflammatory diseases of the PNS.     

A comparison of the myocardial metabolic and haemodynamic changes produced by propofol-sufentanil and enflurane-sufentanil anaesthesia for patients having coronary artery bypass graft surgery

The purpose of this study was to compare propofol-sufentanil with enflurane-sufentanil anaesthesia for patients undergoing elective coronary artery bypass graft (CABG) surgery with respect to changes in (1) haemodynamic variables; (2) myocardial blood flow and metabolism; (3) serum cortisol, triglyceride, lipoprotein concentrations and liver function; and (4) recovery characteristics. Forty-seven patients with preserved ventricular function (ejection fraction greater than 40%, left ventricular end diastolic pressure less than or equal to 16 mmHg) were studied. Patients in Group A (n = 24) received sufentanil 0.2 microgram.kg-1 and propofol 1-2 mg.kg-1 for induction of anaesthesia which was maintained with a variable rate propofol (50-200 micrograms.kg-1.min-1) infusion and supplemental sufentanil (maximum total 5 micrograms.kg-1). Patients in Group B (n = 23) received sufentanil 5 micrograms.kg-1 for induction of anaesthesia which was maintained with enflurane and supplemental sufentanil (maximum total 7 micrograms.kg-1). Haemodynamic and myocardial metabolic profiles were determined at the awake-sedated, post-induction, post-intubation, first skin incision, post-sternotomy, and pre-cardiopulmonary bypass intervals. Induction of anaesthesia produced a larger reduction in systolic blood pressure in Group A (156 +/- 22 to 104 +/- 20 mmHg vs 152 +/- 26 to 124 +/- 24 mmHg; P less than 0.05). No statistical differences were detected at any other time or in any other variable including myocardial lactate production (n = 13 events in each group), time to tracheal extubation and time to discharge from the ICU. We concluded that, apart from hypotension on induction of anaesthesia, propofol-sufentanil anaesthesia produced anaesthetic conditions equivalent to enflurane-sufentanil anaesthesia for CABG surgery.     

Erk activation is required for Nrf2 nuclear localization during pyrrolidine dithiocarbamate induction of glutamate cysteine ligase modulatory gene expression in HepG2 cells.

Pyrrolidine dithiocarbamate (PDTC) induction of the human glutamate cysteine ligase modulatory (GCLM) gene is dependent on activation of the mitogen-activated protein kinases (MAPKs) extracellular regulated kinase (Erk) and p38, and is not affected by protein kinase C (PKC) or PI3K inhibitors. Nrf2 binding to the electrophile response element (EpRE) located within the GCLM promoter is decreased after MAPK inhibition, suggesting that Nrf2 could be a downstream target of activated MAPK. To evaluate this hypothesis, a series of Nrf2 proteins harboring mutations in conserved consensus MAPK phosphorylation sites were developed and used in multiple functional assays. All mutated Nrf2 proteins tested interacted with the cytoplasmic repressor Keap1 in a manner indistinguishable from wild-type Nrf2. Furthermore, the mutant and wild-type Nrf2 proteins were similarly capable of transactivating an EpRE-containing GCLM/luciferase reporter transgene. Collectively these functional assays suggest that Nrf2 is not likely to be a direct downstream target of activated MAPK in vivo. However, treatment of HepG2 cells with MAPK inhibitors PD98059 and/or SB202190 prior to exposure to PDTC, reduced Nrf2 translocation to the nucleus, suggesting that MAPK-directed phosphorylation is a requirement for nuclear localization during PDTC induction of GCLM gene expression.     

RSR13 plus cranial radiation therapy in patients with brain metastases: comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database.

PURPOSE: This phase II, open-label, multicenter study assessed the efficacy and safety of the potential radiation enhancer RSR13 plus cranial radiation therapy (RT) in patients with brain metastases. The primary end point was patient survival in comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database (RTOG RPA BMD). PATIENTS AND METHODS: Eligibility criteria were age > or = 18 years, Karnofsky performance score > or = 70, and brain metastases with solid tumor histology. Patients received cranial RT, 30 Gy in 10 fractions of 3 Gy each, preceded by RSR13, 50 to 100 mg/kg intravenously over 30 minutes. Univariate and multivariate comparisons of survival and cause of death were made between class II study patients and RTOG BMD patients. RESULTS: Fifty-seven RPA class II patients were enrolled. With a minimum follow-up of 24 months, the median survival time and 1- and 2-year survival rates were 6.4 months, 23%, and 11% for the RSR13-treated patients compared with 4.1 months, 15%, and 3% for the RTOG BMD patients (P =.0174). In an exact-matched case analysis (n = 38), median survival time for RSR13 patients was 7.3 months versus 3.4 months for the RTOG BMD patients (P =.006). There was a 54% reduction in the risk of death for RSR13 patients (P =.0267). RSR13-related adverse events of greater than or equal to grade 3 toxicity that occurred in more than one patient included hypoxia, headache, anemia, fatigue, hypertension, and intracranial hypertension. CONCLUSION: RSR13 plus cranial RT resulted in a significant improvement in survival, as well as a reduction in death due to brain metastases, compared with class II patients in the RTOG BMD.     

Impact of Generalist Care Managers on Patients with Diabetes

Objective. To determine how the addition of generalist care managers and collaborative information technology to an ambulatory team affects the care of patients with diabetes.
Study Setting. Multiple ambulatory clinics within Intermountain Health Care (IHC), a large integrated delivery network.
Study Design. A retrospective cohort study comparing diabetic patients treated by generalist care managers with matched controls was completed. Exposure patients had one or more contacts with a care manager; controls were matched on utilization, demographics, testing, and baseline glucose control. Using role-specific information technology to support their efforts, care managers assessed patients' readiness for change, followed guidelines, and educated and motivated patients.
Data Collection. Patient data collected as part of an electronic patient record were combined with care manager-created databases to assess timely testing of glycosylated hemoglobin (HbA1c) and low-density lipoprotein (LDL) levels and changes in LDL and HbA1c levels.
Principal Findings. In a multivariable model, the odds of being overdue for testing for HbA1c decreased by 21 percent in the exposure group ( n =1,185) versus the control group ( n =4,740). The odds of being tested when overdue for HbA1c or LDL increased by 49 and 26 percent, respectively, and the odds of HbA1c <7.0 percent also increased by 19 percent in the exposure group. The average HbA1c levels decreased more in the exposure group than in the controls. The effect on LDL was not significant.
Conclusions. Generalist care managers using computer-supported diabetes management helped increase adherence to guidelines for testing and control of HbA1c levels, leading to improved health status of patients with diabetes.