Medication development of ibogaine as a pharmacotherapy for drug dependence.

The potential for deriving new psychotherapeutic medications from natural sources has led to renewal interest in rain forest plants as a source of lead compounds for the development of antiaddiction medications. Ibogaine is an indole alkaloid found in the roots of Tabernanthe iboga (Apocynaceae family), a rain forest shrub that is native to equatorial Africa. Ibogaine is used by indigenous peoples in low doses to combat fatigue, hunger and in higher doses as a sacrament in religious rituals. Members of American and European addict self-help groups have claimed that ibogaine promotes long-term drug abstinence from addictive substances, including psychostimulants and cocaine. Anecdotal reports attest that a single dose of ibogaine eliminates withdrawal symptoms and reduces drug cravings for extended periods of time. The purported antiaddictive properties of ibogaine require rigorous validation in humans. We have initiated a rising tolerance study using single administration to assess the safety of ibogaine for treatment of cocaine dependency. The primary objectives of the study are to determine safety, pharmacokinetics and dose effects, and to identify relevant parameters of efficacy in cocaine-dependent patients. Pharmacokinetic and pharmacodynamic characteristics of ibogaine in humans are assessed by analyzing the concentration-time data of ibogaine and its desmethyl metabolite (noribogaine) from the Phase I trial, and by conducting in vitro experiments to elucidate the specific disposition processes involved in the metabolism of both parent drug and metabolite. The development of clinical safety studies of ibogaine in humans will help to determine whether there is a rationale for conducting efficacy trials in the future.

Incidence of clostridial contamination in donors' musculoskeletal tissue.

Reports of infection by Clostridium sordellii associated with allograft transplantation have generated considerable interest. We report our experience in recognising clostridial contamination in cadaver donors of musculoskeletal tissue. Tissues obtained from 795 consecutive donors were excised using standard surgical techniques. Samples of blood and bone marrow were also obtained. Donors with clostridia recovered from any site were matched with the preceding donor without clostridia as a procedural and environmental control. The histories of the donors were analysed to determine which variables had a relationship to contamination by running a contingency table and chi-squared test on the variables against the event of a donor being contaminated. Sixty-four donors (8.1%) had clostridia, most commonly C. sordellii. Clostridia were grown from the blood, marrow and tissue samples of 52, 37 and 30 donors, respectively. In eight cases, they were cultured from the tissue samples alone. There was no significant difference in age or gender between the contaminated donors and the control group. Open wounds were more common in control than in contaminated subjects, but only death by drowning in the contaminated group was statistically significant (p = 0.02). The time between death and the excision of tissue which was contaminated (16 hrs 10 mins) compared with control (11 hrs 10 mins) donors was also significant (p < 10(-6)). We conclude that there is clostridial contamination in a significant number of tissue donors, particularly with increasing time between death and tissue excision. Among the most commonly encountered species is C. sordellii. Multiple microbiological cultures, including blood, are necessary in order to identify clostridial contamination.

Neonatal appendicitis: ischemic infarction in incarcerated inguinal hernia.

A premature 12-day-old infant with ischemic infarction of the appendix due to hernial incarceration is presented. Literature review (1901-1975) of 106 cases of acute appendicitis in the first 30 days of life permitted tabulation of some clinical aspects in 94 cases. Overt manifestations mandating surgical intervention and isolation of the inflammatory process in the inguinoscrotal region are important factors responsible for the significantly better prognosis for neonatal hernial versus intraabdominal appendicitis.

Congenital neurogenous sarcoma with rhabdomyosarcomatous differentiation.

A congenital malignant peripheral nerve sheath tumor contained small rhabdomyosarcomatous portions in both the retroperitoneal pelvic primary and in the subpleural lung metastasis. There was no family history of Von Recklinghausen's disease. Of the 10 patients with this tumor previously reported, the youngest is 14 yr old, and eight had familial neurofibromatosis.

Necrotizing enterocolitis in the unfed infant.

From 1974 to 1981, 139 infants with neonatal necrotizing enterocolitis (NEC) were treated at our institution. Fourteen of these infants had not been fed prior to development of NEC. The unfed infants who developed intestinal necrosis had lower birth weights, were less mature, and had lower Apgar scores. The incidence of respiratory distress syndrome (RDS) and perinatal asphyxia were significantly higher in the entire unfed group. Unfed infants generally had longstanding indwelling umbilical artery catheters. Pneumatosis intestinalis was not often seen in unfed infants, even in those who developed intestinal necrosis and perforation. Anatomic location of the disease as determined at surgery was sometimes atypical. The pathologic lesion present in the intestine of the unfed infant suggested a primarily, if not purely, ischemic etiology.

The potential for HIV transmission through allogeneic bone. A review of risks and safety.

Over the past two decades, oral and maxillofacial surgeons have gained a greater appreciation for the biology of allogeneic bone healing, resulting in a dramatic increase in its indications and use. Unfortunately, this time period has also ushered in near epidemic proportions of HIV-infected persons, some of whom might be considered as potential donors of allogeneic bone. As this article will discuss, surgeons and tissue bank teams alike must be aware of the clinical and serologic criteria associated with an acceptable donor. Only in this way can contamination-free specimens be obtained and surgically implanted.

Thanatophoric dwarfism. Two case reports and survey of the literature.

Thanatophoric dwarfism is a severe form of short-limbed dwarfism in which cardiorespiratory failure uniformly results in death in the neonatal period. Its radiographic features include markedly flattened vertebral bodies with a typical U-shaped deformity, a flat squat pelvis, and short, bowed extremities with flaring and irregularity of the metaphyses. These characteristic features distinguish this entity from the two other most commonly confused congenital short-limbed forms of dwarism--achondroplasia and achondrogenesis. The distinctions are discussed in the text.

Human bone and tissue allografts. Preparation and safety.

Currently, modern tissue banks routinely supply requested bone and soft-tissue allografts. These allografts are safe if tissue-bank personnel adhere to the existing methodology for excluding any donors with potential for disease transmission. The authors' discard rate after excision of tissues has been approximately 18%, reflecting their concern for allograft safety. The preparation of significant numbers of allografts is labor intensive and very expensive, as is multiphasic screening of donors. However, long-term success with a large number of bone or soft-tissue recipient patients has led physicians and patients to have confidence in the safety of allografts prepared as described.

Autopsy findings and syndromic diagnoses: Bayesian calculations for pediatric pathologists.

Application of a standard statistical method known as a Bayesian calculation to the findings in pediatric anatomic pathology may help the pediatric pathologist to recognize and express the likelihood of syndromic diagnoses. This assessment can be useful in counseling and deciding which (if any) confirmatory tests are warranted. An example shows the method and its utility.

Primary intimal fibroplasia in a child with Down's syndrome.

A 14-year-old girl known to have trisomy 21 and who came to us with weight loss followed by hypertension proved to have diffuse arterial dysplasia involving the intimal layer (primary intimal fibroplasia). This is a rare cause of elevated blood pressure in children and has not been previously reported in a child with Down's syndrome. Unusual features of this case also include the widespread distribution of the lesions limited to the large muscular distributing arteries, the rapidly progressive course, and the predominance of abdominal signs and symptoms.

Carcinoembryonic antigen in fetal eccrine glands: an immunohistochemical study.

Developing fetal eccrine glands were examined for the presence of carcinoembryonic antigen (CEA) using an unlabeled antibody peroxidase-antiperoxidase technique and rabbit antibody to human CEA. The earliest sign of commitment to the formation of an eccrine gland was the presence of CEA within a single keratinocyte in fetal epidermis. As the eccrine unit evolved, we found CEA in both acrosyringeal cells and the ductal cells. Although the function of CEA in eccrine gland remains undefined, this substance may play an integral role in the earliest development of the gland as well as in its normal function in the adult.

Bone transplantation and human immunodeficiency virus. An estimate of risk of acquired immunodeficiency syndrome (AIDS).

The possibility of transplanting a bone allograft from a donor infected with human immunodeficiency virus (HIV) is remote, provided there is a combination of rigorous donor selection and exclusion, screening for the HIV antigen and antibody, and histopathologic studies of donor tissues. The chance of obtaining a bone allograft from an HIV-infected donor who failed to be excluded by the above techniques is calculated to be one in well over a million, using average estimates. On the other hand, if adequate precautions are not taken (for example, by testing only for antibodies to HIV), the risk might be as high as one in 161.

Single coronary artery originating from the right pulmonary artery.

An infant with a single coronary artery originating from the right pulmonary artery branch is the subject of this report. He survived to the age of one month possibly because of the association of two ventricular septal defects. While the pulmonary vascular resistance remained high, perfusion of the heart muscle was accomplished due to the pulmonary hypertension. The electrocardiogram did not show typical signs of infarction, but poor left ventricular contractility was observed by echocardiogram. The diagnosis was made postmortem. This specific coronary malformation has not been previously described and needs to be included in the classification of congenital coronary arteries anomalies.

Juvenile spindle cell carcinoma.

Spindle cell carcinoma is an uncommon variant of squamous cell carcinoma that is rarely seen in children. The spindle cell pattern is frequently confused with sarcomas. A case of spindle carcinoma in a 14-year-old boy is presented. He is the youngest patient, to the authors' knowledge, with spindle cell carcinoma of the maxilla. Electron microscopic examination is helpful to define the epithelial nature of the spindle cells and can be performed on formalin-fixed tissue. Electron microscopic examination is essential to formulate an optimal treatment plan.

Human immunodeficiency virus cultured from bone. Implications for transplantation.

This study demonstrates by a virologic culture method that human immunodeficiency virus (HIV) resides in bone. After freezing, some initially positive specimens no longer yielded virus, but those that continued to yield virus were not further altered by subsequent washing, which removed essentially all marrow, or by freeze-drying. The safeguards against potential transmission of HIV by a bone allograft are principally the screening and testing methods previously described, although there may be a further reduction of the remote residual risk by the freezing step in the usual technical sequence for tissue banking by sterile techniques.

Distribution and number of transferrin receptors in Parkinson's disease and in MPTP-treated mice.

Transferrin is a glycoprotein that functions primarily to deliver iron to the cell. Recent studies suggest that the transferrin receptor mediates the intracellular delivery and transport of iron bound to transferrin in the CNS. Iron-catalyzed free radical generation has been proposed as a possible cause of nigral cell death in Parkinson's disease. Our hypothesis is that abnormal iron handling by the transferrin receptor may contribute to the formation of free radical species which catalyze the lipid peroxidation of nigral cell membranes. We have assessed the number of transferrin receptors on membrane fractions prepared from the human striatum from control subjects and patients with Parkinson's disease. Equilibrium-binding studies demonstrated a reversible, saturable, and high-affinity transferrin binding site (KD = 3 nM) in human brain membranes. Regional binding assays indicate that the number of transferrin receptors in the putamen was reduced significantly in Parkinson's disease. The density of transferrin receptors was unaltered in membranes prepared from the caudate nuclei and the globus pallidus. To address the possibility that transferrin receptors are located on dopaminergic terminals, we have examined the distribution and number of transferrin receptors in the striatum of MPTP-treated mice using in vitro autoradiographic methods. In these experiments, the loss of dopaminergic terminals in the striatum was visualized by differential [3H]mazindol uptake site autoradiography. A marked reduction in the density of both transferrin receptors and [3H]mazindol binding sites was observed in the mouse striatum 7 days post-MPTP treatment.(ABSTRACT TRUNCATED AT 250 WORDS)