Evidence of a role for the novel zinc-finger transcription factor ZKSCAN3 in modulating Cyclin D2 expression in multiple myeloma.

Dysregulation of cyclin D2 contributes to the pathogenesis of multiple myeloma, and can occur through translocations that activate MAF/MAFB or MMSET/FGFR3. However, cyclin D2 induction can also be seen in the absence of such translocations, such as in patients with hyperdiploid disease, through unknown mechanisms. In UniGene cluster data-mining and ECgene analysis, we found that zinc-finger with KRAB and SCAN domains 3 (ZKSCAN3), a novel transcription factor, is overrepresented in this malignancy, and three consensus ZKSCAN3 binding sites were found in the cyclin D2 promoter. Analysis of a panel of myeloma cell lines, primary patient samples and datasets from Oncomine and the Multiple Myeloma Genomics Portal (MMGP) revealed expression of ZKSCAN3 messenger RNA (mRNA) in a majority of samples. Studies of cell lines by western blotting, and of primary tissue microarrays by immunohistochemistry, showed ZKSCAN3 protein expression in a majority, and in a manner that paralleled messenger levels in cell lines. ZKSCAN3 overexpression was associated with increased gene copy number or genomic DNA gain/amplification in a subset based on analysis of data from the MMGP, and from fluorescence in situ hybridization studies of cell lines and primary samples. Overexpression of ZKSCAN3 induced cyclin D2 promoter activity in a MAF/MAFB-independent manner, and to an extent that was influenced by the number of consensus ZKSCAN3 binding sites. Moreover, ZKSCAN3 protein expression correlated with cyclin D2 levels in cell lines and primary samples, and its overexpression induced cyclin D2. Conversely, ZKSCAN3 suppression using small hairpin RNAs (shRNAs) reduced cyclin D2 levels, and, importantly, inhibited myeloma cell line proliferation. Finally, ZKSCAN3 was noted to specifically bind to oligonucleotides representing sequences from the cyclin D2 promoter, and to the endogenous promoter itself in myeloma cells. Taken together, the data support the conclusion that ZKSCAN3 induction represents a mechanism by which myeloma cells can induce cyclin D2 dysregulation, and contribute to disease pathogenesis.

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.

[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.

Profiles of nursing home residents with multiple sclerosis using the minimum data set.

This paper profiles nursing home residents with multiple sclerosis (MS) at the time of admission, including sociodemographic characteristics, health status measures, and treatments received. Admission assessments from the Minimum Data Set are used to create these profiles of residents with MS. There are 9,013 admission assessments in the MDS for residents with MS between June 22, 1998 and January 17, 2000 analyzed for this study. Residents with MS are distinctly younger at admission than most nursing home residents, averaging 57.98 years of age. Recently admitted residents with MS are more physically dependent than other nursing home residents and tend to have limited range of motion and loss of voluntary movement About one in three newly admitted residents with MS had some degree of impaired cognitive function. Over one third of residents with MS were depressed at admission, yet only 11.7% of recently admitted residents with MS were evaluated by a licensed mental health specialist This prompts concem about the psychosocial well-being of MS residents in nursing homes.

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.

[Cerebellar vermis hypoplasia with extracerebral involvement (retina, kidney, liver): difficult to classify syndromes]. / Hypoplasies vermiennes avec atteintes extracérébrales (rétine, rein, foie): des syndromes difficiles à classer.

UNLABELLED: Congenital cerebellar vermis hypoplasias diversely associated with retinopathy, nephropathy and hepatopathy are rare syndromes of uncertain nosology. We report three new cases. CASE REPORTS: Case 1. A 3-month-old boy presented a brief nystagmus. At the age of 2 years, he had facial dysmorphia, hypotonia, ataxia, ocular motor apraxia and neurodevelopmental impairment with cerebellar vermis hypoplasia. The electroretinogram showed asymptomatic retinal involvement. At the age of 6 years, he developed chronic renal failure. The diagnosis of familial juvenile nephronophthisis was made by detection of a large homozygous deletion of the NPH1 region. Case 2. A term newborn boy presented apnea, tachypnea, hypotonia, nystagmus, ptosis, lack of visual contact and hepatomegaly. He had facial dysmorphia, bilateral optic coloboma with chorioretinal dysplasia and cerebellar vermis hypoplasia. There were cysts in the kidneys with increased echogenicity and lack of demarcation between the pyramids and the cortex. The liver was hyperechoic with fibrosis. At the age of 15 months, the child had severe developmental delay. He had bouts of fever. A search for a large homozygous deletion of the NPH1 region was negative. Case 3. A term newborn girl presented difficulty to suck, cyanosis, hypotonia and ptosis. Later, the child had a developmental delay. At the age of 6 years, she developed chronic renal failure (nephronophthisis). At the age of 23 years, she presented divergent strabismus, ataxia, mental retardation, slow ocular pursuit and facial dysmorphia. The neuroimaging showed a cerebellar vermis hypoplasia. A search for a large homozygous deletion of the NPH1 region was negative. CONCLUSION: The diagnosis of cerebellar vermis hypoplasia requires searching for retina, kidney and liver involvement. The large homozygous deletion of the NPH1 region has to be investigated if typical familial juvenile nephronophthisis is associated. Because cerebellar vermis hypoplasia with extracerebral involvements (retina, kidney, liver) is part of many different closely related syndromes, a clear molecular classification is necessary for accurate genetic counselling and an early prenatal diagnosis.

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.

[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.

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

Aging in America: challenges and strategies for health care delivery.

This article delineates the current and future trends related to aging in the United States. The demographic and economic forces outlined are ones that will clearly challenge health services leaders and policy-makers in the coming decades. Various policy interventions and strategies currently underway to address the needs of the aging population are described. Shifts in caregiving patterns, the delivery of long-term care services, economics, choices in living arrangements, and managed care programs for the elderly are a few of the issues presented in this article. Health and human services for the elderly will undergo a profound change as the health system continues to adapt itself to the demands of an aging society.

Differences in curriculum emphasis in US undergraduate and generalist residency education programmes.

OBJECTIVES: Little attention has been paid to the differential emphasis undergraduate and graduate medical education programmes place on the broad competencies that will be needed for practice in an increasingly managed health care environment. The purpose of this study was to determine differences in emphasis that undergraduate and primary care graduate medical education programmes are currently placing on 33 broad practice competencies, compared with the emphasis they ideally would like to give them, and the barriers they perceive to curriculum change. DESIGN: Subjects were surveyed by mailed questionnaire. A reminder postcard and follow-up mailing were sent to non-respondents. SETTING: US allopathic medical schools. SUBJECTS: Academic deans identified by the Association of American Medical Colleges (AAMC) and generalist (family medicine, internal medicine, paediatrics and obstetrics-gynaecology) residency programme directors identified by the American Council on Graduate Medical Education (ACGME). RESULTS: Findings revealed that residency programmes placed greater emphasis on the study's broad curriculum topics than did undergraduate medical education programmes. Statistically significant differences were found in current emphasis for 12 topics and ideal emphasis for six topics. Both groups identified an already crowded curriculum and inadequate funding as the top two barriers to curriculum change. CONCLUSIONS: The differences in curriculum emphases and perceived barriers to curriculum change most probably reflect the different realities of undergraduate and graduate medical education programmes, i.e. academics vs. a focus on immediate practice realities.

[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.

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.

Curriculum trends in nurse-midwifery education. Views of program directors.

The purpose of this study was to determine the extent to which nurse-midwifery education programs are addressing the practice competencies that have been recommended by the Pew Health Professions Commission and others as essential for effective practice in the 21st century. This study was part of a larger survey of eleven health professions education programs. The 56 nurse-midwifery program directors whose names and addresses were provided by the American College of Nurse-Midwives were surveyed by mailed questionnaire, with a response rate of 59% (n = 33). The study sought to identify current and ideal emphasis placed on 33 broad topics, most important curriculum topics, and barriers to curriculum change as perceived by respondents. Findings revealed that nurse-midwifery program directors would like to see greater emphasis placed on every topic except one (tertiary/quaternary care). Desired increases ranged from .04 to 1.36. The overall mean rating for all topics was 3.51 for current emphasis (5-point scale) and 4.18 for ideal emphasis, both of which were higher than any other survey group. The greatest desired increases (> 1.00) were for "primary care," "managed care," "use of electronic information systems," and "business management of practice." Respondents identified "primary care," "health promotion/disease prevention," and "accountability for cost-effectiveness and patient outcomes" as the most important topics. The top three barriers to curriculum change were identified as "already crowded curriculum," "inadequate funding," and "limited availability of clinical learning sites," the last being statistically significant compared with other survey groups. Findings indicate that nurse-midwifery program directors perceived that they are adequately addressing most of the curriculum topics, while continuing to focus on the need for curriculum change as the health care environment changes.

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.

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.