Tumor necrosis factor-alpha induces changes in mitochondrial cellular distribution in motor neurons.

Motor neuron (MN) mitochondrial abnormalities and elevation in spinal fluid levels of the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). The mechanism of neuron death in ALS remains unclear, along with the contributions of mitochondrial dysfunction and inflammation in the process. Cell cultures enriched for MN derived from embryonic rat spinal cords were established and directly exposed in vitro to recombinant TNF-alpha for varying lengths of time. Although cytokine exposure for up to 4 days failed to induce MN death, mitochondrial changes were observed shortly after initiating treatment. Our results demonstrate that TNF-alpha induced mitochondrial redistribution toward the soma in MN. We postulate that inflammation may precede, and in fact cause, the mitochondrial changes observed in ALS tissue.

Studies on (H(+)-K+)-ATPase inhibitors of gastric acid secretion. Prodrugs of 2-[(2-pyridinylmethyl)sulfinyl]benzimidazole proton-pump inhibitors.

The synthesis of N-substituted benzimidazole (H(+)-K+)-ATPase or proton-pump inhibitors is described. These compounds were prepared to function as prodrugs of the parent N-H compound and evaluated for their ability to inhibit gastric (H(+)-K+)-ATPase and gastric acid secretion. The prodrugs reported rely on either in vivo esterase hydrolysis for liberation of the parent compound (type I and type II) or require an acid environment for release of the active drug (type III and type IV). The N-(acyloxy)alkyl-substituted benzimidazoles 9, 11, and 24 showed improved chemical stability in the solid state and in aqueous solutions when compared to their parent N-H compounds. When given orally, 24 was found to be twice as potent as omeprazole in both the Shay rat and inactivation of gastric (H(+)-K+)-ATPase in the rat. The N-ethoxy-1-ethyl-substituted benzimidazoles 48-50 were found equally as effective as the N-H compound for inhibition of rat (H(+)-K+)-ATPase activity. In the Shay rat 48 at 10 mg/kg was approximately twice as active as parent timoprazole.

Substituent effects on the antibacterial activity of nitrogen-carbon-linked (azolylphenyl)oxazolidinones with expanded activity against the fastidious gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis.

A series of new nitrogen-carbon-linked (azolylphenyl)oxazolidinone antibacterial agents has been prepared in an effort to expand the spectrum of activity of this class of antibiotics to include Gram-negative organisms. Pyrrole, pyrazole, imidazole, triazole, and tetrazole moieties have been used to replace the morpholine ring of linezolid (2). These changes resulted in the preparation of compounds with good activity against the fastidious Gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. The unsubstituted pyrrolyl analogue 3 and the 1H-1,2,3-triazolyl analogue 6 have MICs against H. influenzae = 4 microgram/mL and M. catarrhalis = 2 microgram/mL. Various substituents were also placed on the azole moieties in order to study their effects on antibacterial activity in vitro and in vivo. Interesting differences in activity were observed for many analogues that cannot be rationalized solely on the basis of sterics and position/number of nitrogen atoms in the azole ring. Differences in activity rely strongly on subtle changes in the electronic character of the overall azole systems. Aldehyde, aldoxime, and cyano azoles generally led to dramatic improvements in activity against both Gram-positive and Gram-negative bacteria relative to unsubstituted counterparts. However, amide, ester, amino, hydroxy, alkoxy, and alkyl substituents resulted in no improvement or a loss in antibacterial activity. The placement of a cyano moiety on the azole often generates analogues with interesting antibacterial activity in vitro and in vivo. In particular, the 3-cyanopyrrole, 4-cyanopyrazole, and 4-cyano-1H-1,2,3-triazole congeners 28, 50, and 90 had S. aureus MICs

Pyrimidine thioethers: a novel class of HIV-1 reverse transcriptase inhibitors with activity against BHAP-resistant HIV.

A series of pyrimidine thioethers was synthesized and evaluated for inhibitory properties against wild-type HIV-1 reverse transcriptase (RT) and an RT carrying the resistance-conferring mutation P236L. Modifications of both the pyrimidine and the functionality attached through the thioether yielded several analogues, which demonstrated activity against both enzyme types, with IC50 values as low as 190 nM against wild-type and 66 nM against P236L RT. Evaluation of a select number of pyrimidine thioethers in cell culture showed that these compounds have excellent activity against HIV-1IIIB-WT and retain good activity against a laboratory-derived HIV-1MF delavirdine-resistant variant.

Development of striatal patch/matrix organization in organotypic co-cultures of perinatal striatum, cortex and substantia nigra.

Organotypic cultures of fetal or early postnatal striatum were used to assess striatal patch formation and maintenance in the presence or absence of dopaminergic and glutamatergic influences. Vibratome-cut slices of the striatum prepared from embryonic day 19 to postnatal day 4 rat pups were maintained in static culture on clear membrane inserts in Dulbecco's modified Eagle's medium/F12 (1:1) with 20% horse serum. Some were co-cultured with embryonic day 12-16 ventral mesencephalon and/or embryonic day 19 to postnatal day 4 cortex, which produced a dense dopaminergic innervation and a modest cortical innervation. Donors of striatal and cortical tissue were previously injected with bromo-deoxyuridine (BrdU) on embryonic days 13 and 14 in order to label striatal neurons destined to populate the patch compartment of the striatum. Patches of BrdU-immunoreactive cells were maintained in organotypic cultures of late prenatal (embryonic days 20-22) or early postnatal striatum in the absence of nigral dopaminergic or cortical glutamatergic influences. In slices taken from embryonic day 19 fetuses prior to the time of in vivo patch formation, patches were observed to form after 10 days in vitro, in 39% of nigral-striatal co-cultures compared to 6% of striatal slices cultured alone or in the presence of cortex only. Patches of dopaminergic fibers, revealed by tyrosine hydroxylase immunoreactivity, were observed in the majority of nigral-striatal co-cultures. Immunostaining for the AMPA-type glutamate receptor GluR1 revealed a dense patch distribution in nearly all cultures, which developed in embryonic day 19 cultures after at least six days in vitro. These findings indicate that striatal patch/matrix organization is maintained in organotypic culture, and can be induced to form in vitro in striatal slices removed from fetuses prior to the time of in vivo patch formation. Furthermore, dopaminergic innervation from co-cultured pieces of ventral mesencephalon enhances patch formation in organotypic cultures.

Academic deans' views on curriculum content in medical schools.

PURPOSE: To determine which of 33 topics academic deans identify as worthy of greater emphasis in medical curricula. Also, to assess the barriers to needed curricular changes. METHOD: In March 1996 a questionnaire was developed and mailed to the academic deans of all U.S. schools affiliated with the Association of American Medical Colleges (n = 126) and all schools associated with the American Association of Colleges of Osteopathy (n = 17). There were 46 questions in a five-point Likert-type format (1 = not at all, 5 = to a great extent) and one open-ended question. The deans were queried as to what extent each of 33 topics (1) was included in medical students' required learning experiences (current emphasis) and (2) should be included in medical students' required learning experiences (ideal emphasis). The deans were also asked to what extent they believed 12 different factors would be barriers to needed curriculum changes in their programs. Primary data analysis focused on simple comparisons of response means and frequencies. RESULTS: Two separate mailings resulted in the return of 100 questionnaires (70%): 85 from the allopathic schools (67%) and 15 from the osteopathic schools (88%). "Effective patient-provider relationships/communication," "outpatient/ambulatory care," and "health promotion/disease prevention" had the three highest mean ratings for ideal emphasis by the allopathic school deans. "Primary care," "professional values," and "use of electronic information systems" also had high mean rankings for ideal emphasis. "Primary care," "outpatient/ambulatory care," and "health promotion/disease prevention" had the three highest mean ratings for ideal emphasis by the osteopathic school deans. CONCLUSION: Changes in health care delivery and an increasing generalist orientation are influencing academic deans' perspectives on needed curriculum changes, and there appears to be considerable support for medical school curricula that will foster a broader, more humanistic role for physicians.

Working with community organizations to evaluate potential disease clusters.

Increasingly, private citizens are organizing themselves to resist the intrusion of hazardous substances in their residential environments, or to promote the removal of the same. This movement is the source of the acronym (NIMBY-Not In My Back Yard). In North Carolina, the Cancer Surveillance Section has several experiences working with such community organizations. We have developed a commentary of our experience and observations on some of the characteristics that are more conductive to successful endeavors to resolve perception of increased health risk. Advantages and disadvantages of joint (health agency/concerned citizens group) studies or surveys are described. A case study of a successful joint survey to ascertain possible increased cancer incidence is described.

Environmental health in medical school curricula: views of academic deans.

Academic deans at 126 US medical schools were surveyed in Spring 1994. Comparisons of means and frequencies, multiple regression, and factor analysis were used. Study results showed only low to moderate expectations for graduate competence in seven environmental health competency areas. Over two-thirds of deans (70%) indicated that there was "minimal" emphasis on environmental health at their schools; 61% thought that ideally there should be "moderate" emphasis. An "already crowded curriculum" and "too few qualified faculty" were frequently cited as barriers to greater emphasis on environmental health. Students were identified most commonly as the group expressing the greatest support for environmental health education. Although there was not a clear consensus, occupational medicine departments were most often selected as best suited to offer environmental medicine education.

Environmental health training: a survey of family practice residency program directors.

BACKGROUND: The Institute of Medicine and the American College of Physicians have advocated that physicians broaden their participation in the environmental aspects of medical care. Accordingly, both organizations recommend training of future primary care physicians for greater competency in and appreciation of this area of medicine. This study assessed the present emphasis on environmental health in family practice residency programs by examining the extent program directors expect graduates to have specific competencies in environmental medicine. METHODS: A written survey was mailed to directors of all 393 family practice residency programs listed in the 1993 Directory of Family Practice Residency Programs. Respondents were asked to indicate the extent to which each of eight environmental health competencies was expected of their graduates. The list of environmental health competencies was based on the literature and on interviews with family practice educators. Perceptions about the "present" and "ideal" environmental health emphasis in their programs were also measured. RESULTS: A total of 262 completed surveys were returned for a response rate of 67%. Respondents reported that they expected their graduates to have general knowledge of and competence in environmental health areas that pertain to patient care. Competencies with social and political implications were least likely to be expected. Two thirds of respondents indicated that "minimal emphasis" is presently placed on environmental health. Seventy percent indicated that the "ideal" amount of emphasis placed on this topic is "moderate." CONCLUSIONS: This survey's results suggest that family practice residency program directors expect their graduates to know basic environmental health concepts and be skilled in related aspects of patient care. The development of environmental health training programs must take into account that environmental health may be viewed as a topic of secondary importance and that in most residencies, faculty expertise in this area is limited. For this reason, a self-tutoring strategy, aimed toward the educational needs of both faculty and residents, is recommended.

Sedation and analgesia.

The control of pain and the alleviation of anxiety are integral components in the management of soft tissue injuries in the Emergency Department. Pharmacologic agents utilized for analgesia and sedation must possess properties favorable for emergency department use. This article reviews the pharmacologic approach to patients who require sedation and/or analgesia for the management of a soft tissue injury in the Emergency Department.

Spirituality and healthcare organizations.

In recent years, the place of spirituality in organizations has become increasingly discussed and advocated. On a personal level, this may involve achieving personal fulfillment or spiritual growth in the workplace. In the broader sense, spirituality is considered by many to be essential in an organization's interactions with employees, customers, and the community. This article describes a possible role for greater spirituality in healthcare organizations, whose cultures in recent decades have largely excluded spirituality or religiousness. This is the consequence of an analytical, scientific perspective on human health; a reductionist paradigm in biomedical research; and the inevitable bureaucratization occurring in large healthcare organizations. However, in recent decades, numerous scientific articles supporting a connection between faith or religiousness and positive health outcomes have been published. Because individuals seek meaning when experiencing severe illnesses, and humans universally respond to compassion and caring, spirituality among healthcare workers and managers appears highly appropriate. The article describes organizational barriers to the greater inclusion of spirituality in healthcare and presents several approaches to developing a more caring organization. These include eliciting extensive input from all staff and clinicians in identifying core or common values, ethics, and a philosophy of caring. Programs should ensure that the views of nonreligious staff and patients are respected and that clear guidelines are established for the extent and nature of affective or spiritual support for patients.

Environmental health competencies: a survey of U.S. nurse practitioner programs.

Because of widespread public and governmental concern about the health effects of environmental hazards and exposure in recent years, and the increasing incidence of environmentally-induced diseases, it is important that primary care nurse practitioners possess the knowledge and skills to effectively address environmental health as a component of their practice. A mailed questionnaire survey of 187 U.S. nurse practitioner (NP) programs was conducted, with a response rate of 64%, to determine: 1) current and ideal emphasis on environmental health, 2) faculty preparation for teaching environmental health, 3) environmental health competencies expected of graduates, 4) didactic and clinical contact hours devoted to environmental health, and 5) barriers and incentives to greater emphasis on environmental health. Findings reveal that more than two-thirds of NP program directors believe there should be greater emphasis on environmental health in their programs, but expressed concerns about overcrowded curricula and lack of faculty preparation as barriers to change. Competencies with the highest mean ratings included understanding the relationship between environmental hazards and human health, accessing information resources related to environmental hazards and health, and counseling clients about how they can reduce risks associated with environmental hazards. The two factors identified as most likely to increase the emphasis on environmental health in NP programs were having nurse faculty with expertise and being able to access information resources related to environmental health. Currently, insufficient attention is given to environmental health in nurse practitioner education programs.

Curriculum trends in nurse practitioner programs: current and ideal.

The purpose of this study was to ascertain the extent to which nurse practitioner (NP) education programs are addressing curriculum topics related to practice competencies needed for the next century as recommended by the Pew Health Professions Commission and other professional organizations, including the American Association of Colleges of Nursing and the National Organization of Nurse Practitioner Faculties. The study was part of a comprehensive survey of 11 health professions education programs. NP program directors indicated greatest dissatisfaction with curriculum coverage of "use of electronic information systems" and "business management of practice." The three most important curriculum topics identified by respondents were "primary care," "health promotion/disease prevention," and "effective patient-provider relationships/communication," identical to the three topics rated most important by all groups combined. The most significant barriers to change identified by the respondents included "an already crowded curriculum" and "limited availability of clinical learning sites." Findings show that NP program directors perceive that they are doing an effective job addressing most of the 33 curriculum topics, but they also recognize a need to continue to improve their curricula in response to the ever-changing health care environment. Barriers to achieving the desired curricular improvements, however, may be significant. Recommendations for overcoming these barriers to change are offered.

Academic deans' perceptions of current and ideal curriculum emphases.

This study assessed the current and ideal for dental curriculum emphasis of thirty-three curriculum topic areas and evaluated barriers to curriculum change. A forty-six item survey was mailed to the academic deans of all U.S. dental schools with an 86 percent e response rate (n = 57). The means of their responses for current curricular emphasis and ideal emphasis on the thirty-three topic areas were compared. "Health promotion/disease prevention," "primary care," and "effective patient-provider relationships/communication" were the three topic areas rated most highly (for ideal emphasis) by the academic deans. "Case management," "outpatient/ambulatory care," and "continuous quality improvement" also received high mean scores for ideal emphasis. The most significant barrier to curriculum reform was "an already crowded curriculum." The academic deans reasserted the traditional emphasis in dentistry on primary care. There also appears to be considerable support for educational programs that will foster better patient relationships and greater quality assurance and control.

[Severe forms of eosinophilic meningitis in infants of Mayotte. Apropos of 3 cases]. / Formes graves de méningites à éosinophiles chez le nourrisson à Mayotte. A propos de 3 observations.

BACKGROUND: Eosinophilic meningitis caused by Angiostrongylus cantonensis is widespread in Southeast Asia and the Pacific islands. Adults develop transient meningitis with a benign course, whilst severe or fatal disease may occur in pediatric patients. CASE REPORTS: Three infant girls, aged 8 to 11 months, living on the island of Mayotte, developed fever, hypotonia, coma (2 cases), and, for one of them, seizures. Eosinophilia was detected in the peripheral blood and cerebrospinal fluid. Secondary, flaccid quadraplegia (1 case) or paraplegia (2 cases) with absence of deep tendon reflexes, urinary retention and anal incontinence were noted. Three patients had autonomic dysfunction. Computerized tomography showed enlarged ventricles and cerebral subarachnoid spaces. One patient had sequelae. Two patients could not be followed. Retrospectively, the diagnosis of angiostrongylus infection was established for two infants by a serological study. CONCLUSION: We report three new cases of infants with severe Angiostrongylus cantonensis infection in the French island of Mayotte (Comoro Islands). In this Indian Ocean area, eosinophilic meningitis seems to occur exclusively in infants and with severe radiculomyeloencephalitic forms.

[Angiostrongylus in the infant at Reunion and Mayotte. Apropos of 3 cases of eosinophilic meningitis including 1 fatal radiculomyeloencephalitis with hydrocephalus]. / L'angiostrongylose chez le nourrisson à la Réunion et à Mayotte. A propos de trois méningites à éosinophiles dont une radiculomyéloencéphalite avec hydrocéphalie fatale.

BACKGROUND: Eosinophilic meningitis caused by Angiostrongylus cantonensis is widespread in Southeast Asia and Pacific islands. Adults develop a transient meningitis with a benign course but severe or fatal disease may occur in pediatric patients. CASE REPORT 1: A 11 months old boy living in Mayotte island was hospitalized some days after fever and skin rash with seizure status, coma, flaccid quadriplegia, absence of deep tendon reflexes, urinary retention and anal incontinence. Eosinophilia was observed in peripheral blood and in the cerebrospinal fluid. Secondary, he developed a triventricular hydrocephalus treated by a ventriculoperitoneal shunt. After 3 weeks, the child died. Retrospectively, the diagnosis of angiostrongylus infection was established with the help of serology. CASE REPORTS 2 AND 3: Two infants, 10 and 11 months old boys, living in Reunion island, developed fever and vomitings, irritability and, for one of them, a unilateral sixth cranial nerve palsy. There was eosinophilia in the peripheral blood and in the cerebrospinal fluid. All symptoms progressively disappeared with complete recovery. The suspected diagnosis of angiostrongylus infection was confirmed by the serology. CONCLUSION: We report the first case of Angiostrongylus cantonensis infection in the French island of Mayotte (Comoro Islands) and we confirm the presence of this disease in Reunion island. In this Indian Ocean area, eosinophilic meningitis occurs most of the time in infants with sometimes severe radiculomyeloencephalitic forms. The origin of these occasionally massive infections is the giant African snail Achatina fulica. For a child with meningitis living in Reunion or Mayotte, or coming back from these 2 islands, Angiostrongylus cantonensis infection must be evoked, especially if there is a blood eosinophilia. Since efficiency of antiparasitic treatment is nowadays not proved, information must be given to people living in exposed areas in view to limit incidence of this disease.

[Tuberculous meningitis: value of neuro-imaging for early diagnosis]. / Méningo-encéphalite tuberculeuse: importance de la neuroradiologie pour un diagnostic précoce.

The authors report a case of tuberculous meningoencephalitis diagnosed in a 20-month-old boy with severe neurological sequelae. Most cases of the tuberculous meningitis occur in children less than 3 years old. The mortality rate and incidence of sequelae are greater without early treatment. Imaging has a great impact in the early diagnosis of this disease. In Europe, the increasing incidence of tuberculosis underscores the need to diagnose tuberculous meningitis without delay in children in order to provide a prompt and appropriate treatment.

[Multiple cerebral telangiectasias. Apropos of an anatoma-radioclinical case]. / Télangiectasies cérébrales multiples. A propos d'un cas anatomo-radio-clinique.

UNLABELLED: Telangiectasias are vascular malformations corresponding to dilated capillary separated by nervous parenchyma. They are generally asymptomatic and discovered during autopsy. CASE REPORT: We describe the case of a 2-year-old girl who was admitted for drowsiness and vomitings with craniomegaly and right hemiparesis. The cerebral imaging demonstrated large amounts of calcium in the region of pons and left thalamus with a contrast enhancement throughout these calcifications. The thalamic lesion was cystic with obstruction of the third ventricle and hydrocephalus. There were multiple calcifications scattered throughout the basal ganglia and the white matter. The latter had a low density on CT and high signal intensity on MRI (T2). The cerebral angiographic study showed a blush in the pons and the thalamus. Clinical course was fluctuating or intermittently progressive. Finally, in spite of radiotherapy and oral corticosteroid treatment, the child became quadriparesic with oculomotor palsy. She suddenly died at age 4 years and 6 months from a hemorrhage of the pons. Neuropathological study showed two clusters of telangiectasias with calcifications in the pons and the thalamus. Other calcified vascular malformations were seen in the white matter and the basal ganglia. Near the lesions, astrocytar gliosis and edema were observed. The white matter was malacic with isolated calcifications. CONCLUSION: Cerebral telangiectasias may be multiple and may produce severe neurologic disorders, occurring in infancy with fluctuating clinical course. Arteriography may show these usually cryptic vascular malformations. This diagnostic should be kept in mind in view to the neuroradiological aspect we report here.

[Pseudo-periodic disease with hyperimmunoglobulinemia D: a never-ending story with probable prenatal onset]. / Pseudomaladie périodique avec hyperimmunoglobulinémie D: une histoire sans fin de début anténatal probable.

UNLABELLED: Diagnosis of inflammatory non-infectious diseases with a neonatal onset is often retrospective. It may lead to aggressive and iatrogenic procedures. PATIENT: A 6-year-old boy was suffering, since birth, from recurrent febrile attacks including rashes, gastrointestinal manifestations and inflammatory joint involvement. This syndrome, partially improved with steroids, could have been of antenatal onset. Since the age of 4 years, the patient is considered as having hyper-IgD syndrome (HIDS). DISCUSSION: HIDS must be distinguished from familial Mediterranean fever. Patients suffer from recurrent fever concomitant to inflammatory joint involvement, abdominal distress, skin lesions, swollen lymph nodes and hepatosplenomegaly (especially seen in children). All patients have high serum IgD (> 100 UI/mL) and IgA levels. Nevertheless, a high IgD level is not specific. Our case could also be part of the CINCA (chronic, infantile, neurological, cutaneous and articular) syndrome, which includes similar early manifestations associated with a constant neurological and frequent ophthalmological involvement and epiphyseal changes; to date, these last three manifestations are not present in our patient. CONCLUSION: HIDS and CINCA syndrome are not known to be modified by any effective therapeutic agent. When presenting at birth, these inflammatory diseases must be considered as entities with a rarely described potential severity.

[Feingold syndrome]. / Syndrome de Feingold.

BACKGROUND: Feingold syndrome is a combination of hand and foot anomalies, microcephaly, tracheo-esophageal fistula, esophageal/duodenal atresia, short palpebral fissures and developmental delay. The most frequent physical findings are clinodactyly of the second and fifth fingers with absent or hypoplastic middle phalanges, and syndactyly of the toes. Inheritance is autosomal dominant (MIM number 164280) with full penetrance concerning hand anomalies, variable expressivity and great intrafamilial variability. CASE REPORT: We report the case of an African boy with duodenal atresia, microcephaly, brachymesophalangy of the second and fifth fingers, unilateral thumb hypoplasia, bilateral syndactyly of toes 2-3 and amesophalangy of the toes. Karyotype was normal. No other member of the family was affected. A fresh mutation is possible. CONCLUSION: Brachymesophalangy affecting mainly the second and fifth fingers and amesophalangy of the lateral toes are cardinal clinical findings in Feingold syndrome. These clinical findings define the syndrome of brachydactyly A4-Temtamy type (MIM 112800), suggesting that brachydactyly A4 would be a partially expressed Feingold syndrome. The incidence of esophageal/duodenal atresia is 29%, including all the known cases. All karyotypes of reported patients were normal.