Hepatic Changes in the Fontan Circulation: Identification of Liver Dysfunction and an Attempt to Streamline Follow-up Screening.

We tried to identify structural and functional liver aberrances in a palliated Fontan population and sought to determine useful screening modalities, in order to propose a screening protocol to detect patients at risk. Twenty nine patients, median age 23.7 years (interquartile range (IQR) 20.5-27.2) and median Fontan interval 19.7 years (IQR 4.5-21.4), were prospectively studied with echocardiography, blood analysis (including serum fibrosis scores Forns, APRI and FIB4), liver imaging (ultrasound (US), Doppler), and shear wave elastography to determine liver stiffness (LS). Laboratory tests predominantly showed abnormal values for gamma-glutamyltransferase. Forns index indicated moderate fibrosis in 29% of patients and correlated with Fontan interval (p = 0.034). US liver morphology was deviant in 46% of patients, with surface nodularity in 21% and nodular hyperplasia in 29%. Doppler assessment of flow velocities was within normal ranges for most patients. LS (mean 10.4 ± 3.7 kPa) was elevated in 96% of our population and higher LS values were significantly related to longer Fontan interval (p = 0.018). Adolescent and adult Fontan patients show moderate signs of liver dysfunction. Usefulness of serum parameters and fibrosis scores in post-Fontan screening remains ambiguous. The high percentage of morphologic liver changes in palliated patients supports the use of US in periodic follow-up. LS likely overestimates fibrosis due to liver congestion, arguing for the need of validation through sequential measurements. Screening should minimally encompass US assessment in combination with selective liver fibrosis scores. The role of LS measurement in Fontan follow-up and liver screening needs to be further elucidated.

Assessing comfort, safety, and patient satisfaction with three commonly used penile compression devices.

OBJECTIVES: To assess the safety, efficacy, comfort, and patient satisfaction with three penile compression devices: the Cunningham clamp, C3, and U-Tex. METHODS: The devices were tested in random order in a multiple-period, crossover study design using a Latin squares configuration. The subjects had undergone radical prostatectomy 6 months or more before the study, had no neurologic or cognitive impairment, and had not undergone radiotherapy. Baseline penile Doppler ultrasonography was followed by ultrasound scanning with each device. In random order, subjects completed a 4-hour pad test, with and without each device, and the questionnaire. RESULTS: Twelve men completed the study. The mean Mini-Mental State Examination score was 29.6 (SD 1.2, range 27 to 30). The mean urine loss at baseline was 122.8 g (SD 130.8). The mean urine loss with each device was 53.3 g (SD 65.7) with the U-Tex, 32.3 g (SD 24.3) with C3, and 17.1 g (SD 21.3) with the Cunningham clamp (P <0.05). No device had an impact on the resistive index; the C3 and U-Tex allowed good cavernosal artery flow, and the Cunningham clamp significantly lowered the distal blood flow velocity (from 12.5 to 7.3 cm/s [left systolic velocity] to 9.5 cm/s [right systolic velocity]) even at the loosest setting. The Cunningham clamp was ranked positively by 10 of 12 men; 2 of 12 men rated the C3 positively; none rated the U-Tex positively. CONCLUSIONS: The Cunningham device was the most efficacious and most acceptable to users, but also contributed to reduced systolic velocity in all men. None of the devices completely eliminated urine loss when applied at a comfortable pressure. Individualized instruction to cognitively capable men is necessary to ensure appropriate application, comfort, and fit.

Excitatory amino acid receptor subtype agonists induce feeding in the nucleus accumbens shell in rats: opioid antagonist actions and interactions with mu-opioid agonists.

Administration of mu-opioid receptor subtype agonists into the nucleus accumbens shell elicits feeding which is dependent upon the normal function of mu-, delta- and kappa-opioid receptors, D(1) dopamine receptors and GABA(B) receptors in the nucleus accumbens shell for its full expression. Whereas the AMPA antagonist, DNQX administered into the nucleus accumbens shell elicits a transient, though intense feeding response, feeding is elicited by excitatory amino acid agonists administered into the lateral hypothalamus. The present study examined whether excitatory amino acid agonists elicited feeding following administration into the nucleus accumbens shell of rats, whether such feeding responses were altered by opioid antagonist pretreatment, and whether such feeding responses interacted with feeding elicited by mu-opioid agonists. Both AMPA (0.25-0.5 microg) and NMDA (1 microg) in the nucleus accumbens shell significantly and dose-dependently increased food intake over 4 h. Both feeding responses were blocked by naltrexone pretreatment in the nucleus accumbens shell. The mu-opioid agonist, [D-Ala(2),NMe-Phe(4),Gly-ol(5)]-enkephalin in the nucleus accumbens shell significantly increased food intake which was significantly enhanced by AMPA cotreatment. This enhanced feeding response was in turn blocked by pretreatment with either general or mu-selective opioid antagonists. In contrast, cotreatment of NMDA and the mu-opioid agonist in the nucleus accumbens shell elicited feeding which was significantly less than that elicited by either treatment alone. These data indicate the presence of important interactions between excitatory amino acid receptors and mu-opioid receptors in the nucleus accumbens shell in mediating feeding responses in nondeprived, ad libitum-fed rats.

The ethics of drug research in children.

The obligation of society to improve the welfare of its members requires the conduct of paediatric drug trials. Nevertheless, research activities must satisfy obligations to individual participants. The obligation to protect the welfare of children requires that nontherapeutic research procedures generally involve no more than minimal risk. It also requires that randomisation occurs only when the relative merits of therapeutic procedures remain unsettled among the relevant community of experts. The duty to respect the developing autonomy of children requires that they be included in decision-making about research participation in a manner consistent with the level of their decision-making capacity. However, when children lack mature decision-making capacities, the duty of parents to protect their welfare may properly constrain their choices. Justice requires that the benefits and burdens of research be distributed in a manner that assures equal opportunity for all children. Vulnerable children should receive special protection against the burdens of nontherapeutic research procedures. The benefits of participating in clinical trials should be available to all children with serious illnesses for which current treatment is unsatisfactory. Justice also requires that initiatives be undertaken to rectify current shortcomings in the scope of paediatric drug research. Striking an appropriate balance between obligations to conduct research and to protect the interests of participants is essential to the moral integrity of paediatric drug research.

The evolution of porcine reproductive and respiratory syndrome virus: quasispecies and emergence of a virus subpopulation during infection of pigs with VR-2332.

GP5, the principal envelope glycoprotein of porcine reproductive and respiratory syndrome virus (PRRSV), contains a hypervariable region within the ectodomain which is responsible for generating diversity in field isolates. The purpose of this study was to gain insight into the possible origin of this diversity by following GP5 sequence changes in pigs exposed to PRRSV strain VR-2332 in utero. A region of the PRRS virus genome containing portions of ORF4 and ORF5 was amplified directly from tissues of infected pigs from birth to 132 days of age. We observed the emergence of a new PRRSV population, identified by a single nucleotide change in the ectodomain. The Asp to Asn change at amino acid 34 was also found as a minor component in pigs that expressed the wild-type sequence. The results from this study suggest that the variability in the ectodomain of ORF5 is the result of positive or negative selection, of which the mechanism remains to be determined.

Atropine and neuromuscular fade in the mouse phrenic nerve-diaphragm.

PURPOSE: These studies were intended to resolve the conflict between the reasonable inference from the scientific literature that atropine might alter neuromuscular fade and the expectation from informal clinical experience that it does not. METHODS: We examined the effect of a high concentration of atropine (20 microM) on moderate neuromuscular block and fade produced by d-tubocurarine (dTC). Isometric twitch tension was measured in the mouse phrenic nerve-diaphragm preparation. In one set of experiments, the phrenic nerve was stimulated with trains of 5 pulses at 10 Hz every second. Block and fade were measured in two groups, control and with atropine (n = 6 each). In another set of experiments, the phrenic nerve was stimulated with standard train-of-four stimulation (TOF, 4 pulses at 2 Hz every 11.5 seconds). Block and fade were measured first in a control period and then in a treatment period with either saline (n = 4) or atropine (n = 4). RESULTS: During 10 Hz train stimulation, atropine had no significant effect on either the block of the first twitch (control: 62 +/- 17; atropine: 75 +/- 4) or fade (control: 55 +/- 12: atropine; 57 +/- 14) produced by dTC. Similarly, atropine did not differ significantly from saline in altering dTC-induced block of first twitch (saline: 92.5 +/- 14; atropine 92.5 +/- 9.6% control) or fade (saline 119 +/- 50; atropine 102 +/- 30% control) during TOF stimulation. CONCLUSIONS: While atropine may alter ACh release under some conditions, its action is not great enough to alter either block or fade.

Chemically dependent physicians and informed consent disclosure.

Developments in law, professional guidelines, and public attitudes support informed consent disclosure by physicians who have been treated for chemical dependency. This view is built on the apparent materiality of the risk of relapse to informed treatment decisions by patients. Several considerations undercut this position. The probability is remote that a patient will be injured by a recovering physician who suffers an undetected relapse while being properly monitored. Monitoring by impaired physicians programs provides a more sensitive and specific mechanism for detecting relapsed physicians. Moreover, compromise of the privacy and employment rights of recovering physicians by consent disclosure is not justified if programs provide rigorous monitoring that protects the welfare of patients. Finally, required consent disclosure will reduce referrals of chemically dependent physicians to impaired physicians programs, thereby increasing the danger to patients. Limiting demands for required consent disclosure necessitates effective operation of impaired physicians programs.

Appropriate and inappropriate prescribing of narcotics for ambulatory HIV-positive patients.

OBJECTIVE: To assess the appropriateness of narcotic-prescribing practices in an ambulatory clinic for patients infected with HIV. DESIGN, SETTING, AND PATIENTS: The medical records of 220 (190 HIV-positive) patients, seen in a clinic primarily designed for the long-term follow-up of ambulatory HIV-infected patients and located in an inner-city, public teaching hospital, were retrospectively reviewed to determine the prevalence and appropriateness of prescribing Drug Enforcement Administration schedule 2 narcotics. Appropriateness was based on published guidelines for the use of narcotics in the treatment of cancer patients. MEASUREMENTS AND MAIN RESULTS: The prevalence of narcotic use among the HIV-positive patients was 15%. Narcotics were prescribed for 38% of the patients who died, 33% of those with AIDS [Centers for Disease Control and Prevention (CDC) clinical class C], 4% of those with AIDS-related complex (ARC) (CDC clinical class B), and 5% of asymptomatic HIV-positive patients (CDC clinical class A). None of the HIV-negative patients seen in the clinic received narcotics. Narcotics were more likely to be prescribed for patients with AIDS than for patients with ARC (p < 0.001) or for HIV-positive patients (p < 0.001). For the three CDC clinical classes, there was no significant difference among the proportions of patients receiving narcotics inappropriately (p = 0.108). Among the risk groups, intravenous drug abusers were more likely to be prescribed narcotics inappropriately than were men who were homosexual (p < 0.001) or individuals who were heterosexual (p = 0.013); transfusion recipients were also more likely to be prescribed narcotics inappropriately than were homosexual men (p = 0.026) or heterosexual men or women (p = 0.032). Narcotics were more likely to be prescribed for patients with disseminated histoplasmosis (p = 0.022), Pneumocystis carinii pneumonia (p = 0.001), candidal esophagitis (p = 0.020), Kaposi's sarcoma (p < 0.001), or wasted appearance (p = 0.043). Inappropriate prescriptions were more likely to be given to patients with dementia (p = 0.005) or wasted appearance (p = 0.019). CONCLUSIONS: Physicians tend to prescribe narcotics inappropriately to patients known to have previously abused drugs and to those who appear wasted or have dementia. Physicians have a duty to prescribe narcotics appropriately as guided by recognized medical indications and the patients' views concerning their current medical needs.

Angiomyolipoma with lymph node involvement.

A renal mass accompanied by adenopathy was found incidentally in an asymptomatic 25-year-old woman. The computed tomography and ultrasonography findings suggested a malignant neoplasm. At pathological examination, however, renal angiomyolipoma was diagnosed; the lesion contained almost no fat and involved the lymph nodes, an unusual presentation for this tumour.

A programme for treating chemically dependent medical students.

The first American programme for chemically dependent medical students at the University of Tennessee, Memphis is described. The goals of the Aid for the Impaired Medical Student (AIMS) Program are to provide confidential treatment for chemically dependent medical students, to assure that recovering students are able to resume their education, and to protect patients and others from the harm that may be caused by impaired students. The Program is administered by the AIMS Council, consisting of medical professionals and elected student representatives. The Council oversees the management of cases, including investigation of students who may be impaired, intervention when chemical dependency is suspected, diagnostic evaluation, treatment and aftercare, and post-recovery advocacy for students. The Program's experience includes 18 cases of suspected chemical dependency, with four self-referrals and 14 students referred by third parties. Eleven students have been diagnosed as chemically dependent and have completed treatment programmes. Nine have maintained recovery and eight have graduated. One student subsequently relapsed and committed suicide. Obstacles in programme implementation have involved absence of perceived need, the view that chemically dependent students should be dismissed from school, and reluctance of students to report classmates. Resources have included highly respected student representatives, a supportive administration, assistance of the impaired physicians programme, and medical insurance and professional courtesy to defray costs. Although the number treated has been modest, the AIMS Program is an important vehicle for training students regarding chemical dependency and their professional obligations toward impaired colleagues.