Triheptanoin treatment in patients with pediatric cardiomyopathy associated with long chain-fatty acid oxidation disorders.

Long-chain fatty acid oxidation disorders (LC-FAOD) can cause cardiac hypertrophy and cardiomyopathy, often presenting in infancy, typically leading to death or heart transplant despite ongoing treatment. Previous data on triheptanoin treatment of cardiomyopathy in LC-FAOD suggested a clinical benefit on heart function during acute failure. An additional series of LC-FAOD patients with critical emergencies associated with cardiomyopathy was treated with triheptanoin under emergency treatment or compassionate use protocols. Case reports from 10 patients (8 infants) with moderate or severe cardiomyopathy associated with LC-FAOD are summarized. The majority of these patients were detected by newborn screening, with follow up confirmatory testing, including mutation analysis; all patients were managed with standard treatment, including medium chain triglyceride (MCT) oil. While on this regimen, they presented with acute heart failure requiring hospitalization and cardiac support (ventilation, ECMO, vasopressors) and, in some cases, resuscitation. The patients discontinued MCT oil and began treatment with triheptanoin, an investigational drug. Triheptanoin is expected to provide anaplerotic metabolites, to replace deficient TCA cycle intermediates and improve effective energy metabolism. Cardiac function was measured by echocardiography and ejection fraction (EF) was assessed. EF was moderately to severely impaired prior to triheptanoin treatment, ranging from 12-45%. Improvements in EF began between 2 and 21days following initiation of triheptanoin, and peaked at 33-71%, with 9 of 10 patients achieving EF in the normal range. Continued treatment was associated with longer-term stabilization of clinical signs of cardiomyopathy. The most common adverse event observed was gastrointestinal distress. Of the 10 patients, 7 have continued on treatment, 1 elected to discontinue due to tolerability issues, and 2 patients died from other causes. Two of the case histories illustrate that cardiomyopathy may also develop later in childhood and/or persist into adulthood. Overall, the presented cases suggest a therapeutic effect of triheptanoin in the management of acute cardiomyopathy associated with LC-FAOD.

White matter damage following systemic injection of the mitochondrial inhibitor 3-nitropropionic acid in rat.

Oxidative stress has been implicated as a pathogenic mediator of neuronal perikarya cell death. Axons and oligodendrocytes, components of white matter, could also be vulnerable to oxidative damage. An experimental model of oxidative stress was induced by systemic injection of 3-nitropropionic acid (3-NPA). Animals received an i.p. injection of 10, 15, 20 or 30 mg/kg 3-NPA or vehicle and were killed 24 h later. 3-NPA produced a concentration-dependent increase in axonal pathology within the striatum reflected by the amount of beta-APP and SNAP-25 accumulation. Axonal damage was anatomically coincident with the neuronal lesion. There was no neuronal or axonal damage in the subcortical white matter or cerebral cortex in any of the animals treated with 3-NPA. Manganese superoxide dismutase (Mn-SOD) immunoreactivity was present in the vehicle and all 3-NPA treated groups. The amount of Mn-SOD cellular staining was concentration-dependently increased within the striatum supporting a role for oxidative stress in the mechanism of 3-NPA neurotoxicity. Oligodendrocyte-like cells within the subcortical white matter were immunopositive for calpain-mediated spectrin breakdown products and increased in a concentration-dependent manner. Therefore in this experimental model, mitochondrial inhibition may lead to the initiation of oxidative stress and calpain activation, which could mediate cytoskeletal breakdown in axons and oligodendrocytes suggesting an interaction between at least two pathogenic mechanisms.

The lipid peroxidation by-product 4-hydroxynonenal is toxic to axons and oligodendrocytes.

Lipid peroxidation and the cytotoxic by-product 4-hydroxynonenal (4-HNE) have been implicated in neuronal perikaryal damage. This study sought to determine whether 4-HNE was involved in white matter damage in vivo and in vitro. Immunohistochemical studies detected an increase in cellular and axonal 4-HNE within the ischemic region in the rat after a 24-hour period of permanent middle cerebral artery occlusion. Exogenous 4-HNE (3.2 nmol) was stereotaxically injected into the subcortical white matter of rats that were killed 24 hours later. Damaged axons detected by accumulation of beta-amyloid precursor protein (beta-APP) were observed transversing medially and laterally away from the injection site after intracerebral injection of 4-HNE. In contrast, in the vehicle-treated animals, axonal damage was restricted to an area immediately surrounding the injection site. Exogenous 4-HNE produced oligodendrocyte cell death in culture in a time-dependent and a concentration-dependent manner. After 4 hours, the highest concentration of 4-HNE (50 micromol/L) produced 100% oligodendrocyte cell death. Data indicate that lipid peroxidation and production of 4-HNE occurs in white matter after cerebral ischemia and the lipid peroxidation by-product 4-HNE is toxic to axons and oligodendrocytes.

Intraventricular infusion of apolipoprotein E ameliorates acute neuronal damage after global cerebral ischemia in mice.

The ability of intraventricular infusion of apolipoprotein E (apoE) to reduce neuronal damage after global cerebral ischemia was investigated in apoE-deficient and wild-type mice. ApoE (5 microg/mL lipid-conjugated derived from human plasma; 1 microL/h, continuous infusion) significantly reduced neuronal damage in the caudate nucleus and CA2 pyramidal cell layer by approximately 50% in apoE-deficient mice after global ischemia compared to vehicle infusion. In wild-type mice infused with apoE, there was a trend for ischemic neuronal damage to be reduced. ApoE-infused mice had a marked reduction in 4-hydroxynonenal immunoreactivity, as a marker of lipid peroxidation. The results show that the presence of apoE at or after the time of injury can be neuroprotective, possibly via an anti-oxidant mechanism.

Calpain activation and cytoskeletal protein breakdown in the corpus callosum of head-injured patients.

Calpain-mediated breakdown of the cytoskeleton has been proposed to contribute to brain damage resulting from head injury. We examined the corpus callosum from patients who died after a blunt head injury in order to determine if there was evidence of these pathophysiological events in a midline myelinated commissure that is susceptible to damage after human head injury. Western blotting revealed marked reductions in the levels of neurofilament triplet proteins 200 and 68kDa in the corpus callosum of head-injured patients compared with control subjects. Neurofilament 200kDa levels were significantly reduced as detected by either phosphorylation-dependent or -independent antibodies. In contrast, there were minimal changes in the levels of beta-tubulin or the microtubule-associated protein, tau, in the head-injured patients, although amyloid precursor protein immunostaining demonstrated axonal damage in 9 of the 10 patients. The inactive 800kDa and active 76kDa subunits of mu-calpain were present in control subjects and head-injured patients. However, there was a significant increase in the levels of calpain-mediated spectrin breakdown products in head-injured patients compared with the control subjects. The results demonstrate that following human blunt head injury, there is a significant degradation of neurofilament proteins and increased levels of calpain-mediated spectrin breakdown products within the corpus callosum. Therefore, our data support the hypothesis that calpain-mediated breakdown of the cytoskeleton may contribute to axonal damage after head injury.

Mechanisms of recovery of swallow after supraglottic laryngectomy.

This study examines oropharyngeal swallow disorders and measures of pharyngeal and laryngeal movement during deglutition from videofluorographic studies of oropharyngeal swallow in 9 patients who had undergone supraglottic laryngectomy and 9 age-matched normal subjects. The swallows of surgical patients were examined at 2 weeks and 3 months postoperatively. Two critical factors in recovery of swallowing were identified: (a) airway closure at the laryngeal entrance, that is, the space between the arytenoid cartilage and the base of the tongue, and (b) the movement of the tongue base to make complete contact with the posterior pharyngeal wall. When patients achieved these two functions, they returned to normal swallowing. The duration of tongue base contact to the posterior pharyngeal wall and extent of anterior movement of the arytenoid increased significantly from 2 weeks to 3 months in the surgical patients. At 2 weeks postsurgery, patients who had undergone supraglottic laryngectomy exhibited significantly shorter airway closure and tongue base to pharyngeal wall contact, reduced laryngeal elevation, increased width of cricopharyngeal (CP) opening, and later onset of airway closure and tongue base movement than normal subjects. These significant differences remained at 3 months postoperatively, although swallow measures were moving toward normal in the patients who had undergone supraglottic laryngectomy. Comparison of patients not eating at 2 weeks with patients at the time of first eating revealed significantly longer duration of tongue base contact to the pharyngeal wall, longer duration of airway closure, and greater movement of the arytenoid in patients who were eating. Results indicate that the focus of swallowing therapy after supraglottic laryngectomy should be on improvement of posterior movement of the tongue base and anterior tilting of the arytenoid to close the airway entrance and improve bolus propulsion (in the case of the tongue base).

Detecting, preventing, and managing patients' alcohol problems.

OBJECTIVE: To examine Canadian family physicians' attitudes, beliefs, and practices regarding alcohol use and alcohol-related problems among their patients. DESIGN: A self-administered questionnaire mailed to a random sample of 2883 family physicians. The survey was conducted using a modified Dillman method. PARTICIPANTS: Canadian physicians in active office-based practice during 1989. Sample included certificated and noncertificated members of the College of Family Physicians of Canada, as well as non-members of the College. MAIN OUTCOME MEASURES: Perceived importance of various health-promotion behaviours; attitudes and beliefs about working with problem drinkers; current knowledge and practices regarding identifying and managing problem drinkers; and demographic characteristics. RESULTS: Respondents had a strong sense of role legitimacy in working with problem drinkers, but predominantly negative and pessimistic attitudes. Half the respondents felt they had failed in their work with problem drinkers. More physicians agreed on a psychosocial etiology for alcoholism than on a biological origin. Three quarters of respondents said they "almost always" ask patients about quantity and frequency of alcohol use, and just over one third "almost always" ask about problems related to drinking. Data also suggest doctors have relatively few patients with alcohol problems, and they need help in responding to such patients. CONCLUSION: Physicians need more training for their role in identifying and managing patients with alcohol problems.

Peripheral prostaglandin metabolite levels in women undergoing therapeutic abortions in the first trimester with and without treatment with prostaglandin synthetase inhibitor.

The levels of 11-deoxy-13,14-dihydro-15-keto-11 beta, 16 xi-cyclo prostaglandin E2 (bicyclo PGEM), 13,14-dihydro-15 keto-prostaglandin F2 alpha (PGFM) and prolactin were measured in four serial plasma samples collected from thirty women undergoing therapeutic abortions in the first trimester by a suction curettage procedure. Eleven of these women received a preoperative loading dose of sodium meclofenamate, a PG synthetase inhibitor, before the abortion procedure was started and the rest received this medication after the last blood samples were drawn. Prolactin levels increased significantly during the procedure. Sodium meclofenamate treatment had no effect on this increase. Bicyclo PGEM levels did not increase during the procedure in untreated or treated women, whereas PGFM levels increased but only in untreated women. The lack of increase in treated women apparently was not a treatment effect because PGFM levels in corresponding samples of untreated and treated women were similar. Treatment significantly reduced the bicyclo PGEM levels immediately after completion of the procedure as compared to untreated women. This differential PG response to treatment is unprecedented and may be due to sodium meclofenamate inhibition of PGE2 and not PGF2 alpha synthesis. Nevertheless, these data demonstrate that sodium meclofenamate treatment of patients undergoing first trimester therapeutic abortion to relieve pain involves selective suppression of PGE2 synthesis.

Peripheral plasma levels of prostaglandin metabolites, cortisol and prolactin in women undergoing falope ring application and tubal cautery.

The levels of 11-deoxy-13,14-dihydro-15-keto-11 beta, 16 xi-cyclo PGE2 (bicyclo PGEM), 13,14-dihydro-15-keto PGF 2 alpha (PGFM), cortisol and prolactin were measured by radioimmunoassays in five serial plasma samples collected from fourteen patients undergoing falope ring application and three patients undergoing tubal electrocautery. Bicyclo PGEM, PGFM and cortisol levels were unchanged regardless of the type of tubal occlusion procedure or the type of anesthesia administered (7 received general and 10 local anesthesia). Prolactin levels, on the other hand, markedly increased. The increase was greatest in women that received general anesthesia. The lack of change in bicyclo PGEM and PGFM in peripheral plasma would suggest a local transfer of PGs produced by injured tubal tissue to other parts of the tube and the uterus resulting in increased contractions and pelvic pain.

The patient-centred clinical method. 3. Changes in residents' performance over two months of training.

A method for assessing the patient-centred approach was used to identify changes taking place in the interviewing behaviour of 13 residents during two months in a teaching practice. The descriptive study confirmed the prediction that the residents' approach would become more patient-centred. A statistically significant change from August to October was found in the number of facilitating behaviours shown by residents (P less than 0.05) and there was a change in the number of fears expressed by patients (P less than 0.10). Increases in the number of expectations, feelings and prompts were noted but were not significant. The frequency with which residents cut off patients' expressions increased on the whole, although not significantly. The findings suggest that while these residents had succeeded in increasing their facilitating behaviours over two months (one-sixth of their family medicine experience) they had not yet found ways of responding to the many problems elicited.

The patient-centred clinical method. 2. Definition and application.

In this article, the patient-centred clinical method is described in operational terms. Definitions are given for the patient's expectations, feelings and fears. The physician behaviours described are: facilitations, acknowledgements, cut-offs and returns. Using the definitions, a method was devised for scoring video-taped interviews for the degree of 'patient-centredness'. The method proved to have good inter-observer reliability.

The patient-centred clinical method. 1. A model for the doctor-patient interaction in family medicine.

This article describes a patient-centred clinical method appropriate for family medicine. The method is designed to attain an understanding of the patient as well as his disease. This two-fold task is described in terms of two agendas: the physician's and the patient's. The key to an understanding of the patient's agenda is the physician's receptivity to cues offered by the patient, and behaviour which encourages him to express his expectations, feelings and fears. The physician's agenda is the explanation of the patient's illness in terms of a taxonomy of disease. In the patient-centred clinical method, both agendas are addressed by the physician and any conflict between them dealt with by negotiation. This is contrasted with the disease-centred method in which only the doctor's agenda is addressed. Further articles will describe the patient-centred method in operational terms.

How family physicians approach ethical problems.

The defining features of family medicine as described in the literature have important ethical implications. In an attempt to study the day-to-day practice of family physicians regarding these ethical issues, a 28-item questionnaire was sent to 95 part-time and 17 full-time family physician teachers associated with the University of Western Ontario's Department of Family Medicine. Of the 112 questionnaires mailed out, 97 were returned for a response rate of 86.6 percent. There was a significant spread of answers, suggesting there is no uniform opinion in the sample population. The findings suggest that there are important differences between the description of family medicine in the literature and what the family physicians in this study do in their day-to-day practice. The family physicians in this study, while prepared to coerce patients, were not prepared to discharge from their practices patients who were noncompliant. Physician age is an important variable in some ethical decisions, but not in others.

Patient-centred care: the family practice model.

The core experience of family practice-the consultation between doctor and patient-is the same for all family physicians, whether they practice in urban, rural or isolated areas. There is not yet a family practice model of this consultation, and the result is wide differences in residency programs' curricula, and residents' perception that their teachers contradict each other. This paper proposes that residents be taught, and practicing family physicians use, a patient-centred method of consultation in which the physician attempts to understand how the patient interprets his illness, as well as to establish the relationship between illness and organic pathology. Two case histories illustrate how this can be done by using open-ended questions and facilitating remarks that encourage the patient to express his feelings.

Illness Following MMR Immunization in Indian and Non-Indian Children.

A cohort study was undertaken to see if the frequency of office reported illness during the three weeks after MMR immunization was greater among Indian children (N=127) compared to non-Indian children (N=81) attending a family practice centre. All children had been given HPV(77)DE(5) vaccine or RA 27/3 vaccine between ages 11 and 24 months. Illness after immunization was not related to frequency of attendance at the medical centre or weight at age 12 months. The overall illness rate for Indian children was almost twice the rate for non-Indians. Indian children who were ill before immunization were more likely to be ill during the three week post-MMR period. No such relationship was noted among non-Indian children. This suggests that children with an established record of frequent illness are likely to experience an illness following MMR immunization. These results need to be confirmed by a prospective study.

Sex and the mentally retarded: is sterilization the answer?

The sexuality of the mentally handicapped concerns them, their parents, their family physicians and other health professionals. Parents need advice, and the well-informed family physician who has the family's trust is in a good position to give it. However, the physician must protect the rights and autonomy of the mentally handicapped patient concerning contraception, surgical sterilization and hysterectomy. Before recommending a method of contraception, the physician must identify any medical risks and be satisfied that the patient clearly understands risks and advantages. Sterilization as a method of contraception should never be considered unless the patient chooses it; involuntary sterilization can produce serious and significant psychological damage. The physician must give a detailed explanation to make sure the patient electing to be surgically sterilized understands the procedure and has fully consented without coercion. Hysterectomy should never be used as a method of sterilization.