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Although mental health problems constitute 8.1% of the global burden of disease (GBD), mental health has been largely missing from the international health agenda. The discrepancy between needs and services is likely to increase in the next millennium. Depression alone is currently the fourth leading cause of disability-adjusted life-years (DALYs) the world over and is projected to become the second leading cause by the year 2020. The nations of the world must make a major commitment to upgrade the quality of mental health services, including early detection and prevention of psychiatric problems in childhood and adolescence; to institute the collection of systematic data on the global burden of alcohol and drug abuse and to develop innovative treatment and preventive measures; and to provide substantial support for research on treatment effectiveness. Because hunger, deprivation, and violence affect women disproportionately, there is a pressing need for coordinated efforts to improve state gender policies (including equal educational opportunity and improved health care for women) and to interdict domestic violence. In the words of Boutros Boutros Ghali, the Secretary General of the United Nations: "Medical and social issues which are often viewed separately must be dealt with as a whole...the priority of mental health must be heightened...development policies must...protect and promote mental health."

Real-ear sound pressure levels (SPLs) were compared among three methods used for positioning a probe microphone in the ear canal. The probe insertion techniques included (1) an acoustic method that incorporates use of the quarter-wave anti-resonance property of the ear to determine acoustically the location of the probe tube relative to the eardrum; (2) a constant insertion depth method (25 mm from the intratragal notch); and (3) the earmold +5-mm method, which places the probe 5 mm beyond the tip of the earmold, thereby avoiding problems associated with the transition region where sound exits from the bore of the earmold into the larger ear canal. Measurements were obtained at 32 test frequencies in 24 adults with normal middle ear impedance. Results indicated that the SPLs measured by the acoustic method were modestly higher than those measured by the other two methods. This result was most evident in subjects with long ear canals (> 25 mm) and at high test frequencies (3.0 to 6.3 kHz).

Objective: The purpose of this article is to review the development of concepts about the contribution of nature and nurture to brain structure and mental function, and to derive the implications of these changing concepts for clinical practice., Method: The literature of the past five decades, as refracted by the author's personal experience in academic psychiatry during that interval, is reviewed., Results: Psychiatric theory has swung through mighty arcs in recent years but has begun to re-equilibrate. Fifty years ago, psychoanalysis dominated the academic scene; for the past two decades, reductionist biological determinism has held the fort. Neither position is tenable. To subscribe to either is possible only by ignoring conflicting evidence. Worse, it means short-changing patients, whose disorders do not come neatly packaged into "organic" and "functional" compartments. Development is neither predestined in the genome nor completely malleable to shaping by the environment. Children inherit, along with their parents' genes, their parents, their peers, and the communities they inhabit., Conclusions: Contemporary psychiatric research conclusively demonstrates that mind/brain responds to biological and social vectors and is jointly constructed by both. Major brain pathways are specified in the genome; detailed connections are fashioned by, and consequently reflect, socially mediated experience in the world. Just at the time when integration at the level of theory is coming into sight, comprehensive patient care is endangered by for-profit corporate managed care, which is transforming medical visits into commodities on a production line. Physicians and patients must join in a coalition to protect quality, ensure access, and build continuity into all of medical care.

Children's subjective judgments of speech clarity using the methods of paired comparisons and category rating were evaluated in this investigation. Eighty children with normal hearing between the ages of 4 and 8 years judged the clarity of sentences that were systematically bandpass-filtered using conditions that increased intelligibility as estimated by the Articulation Index. Subjects were classified into four age groups (4-, 5-, 6-, and 7-8-year age groups) with 20 subjects per group. With use of materials and training methods suitable for children, judgments were obtained via the two psychophysical procedures (10 subjects per age group for each procedure). Results indicated that children 5 years of age and older were able to make reliable clarity judgments using either procedure; however, the method of paired comparisons was more sensitive than category rating in detecting differences between the bandpass-filtered conditions.

The majority of congenital heart defects arise from abnormal development of valvuloseptal tissue. The primordia of the valve leaflets and membranous septa of the heart are the cardiac cushions. Remodeling of the cushions is associated with a transitional extracellular matrix that includes sulfated proteoglycans and the microfibrillar proteins fibulin and fibrillin. Cushion formation is restricted to the AV canal and ventricular outflow tract regions of the primary heart tube. The proper placement of the cushions may be the result of the development of the primary heart tube as a segmented organ, as well as the subsequent looping of the heart. Segmentation of the heart tube may be demonstrated by the alternating molecular expression pattern along the longitudinal axis. In support of this hypothesis is the restricted expression of BMP-4 and msx-2 to the AV canal and ventricular outflow tract. The importance of looping for cushion positioning may imply that the iv and inv genes and retinoic acid are important for the proper patterning of the heart. The cells of the cushions evolve from endocardial cells that undergo an epithelial-to-mesenchymal transformation. This developmental event is regulated by the myocardium and is probably due to the production of protein complexes, present within the cardiac jelly of the cushion-forming regions, that consist of fibronectin and the ES proteins. Both the cushion mesenchyme and its endocardial cell antecedents express JB3, an ECM protein. JB3 expression is also featured within the heart-forming fields of the primary mesoderm, from which the endocardial progenitors of the cushion cells originate.(ABSTRACT TRUNCATED AT 250 WORDS)

Focal nodular hyperplasia (FNH) is a benign liver condition, which generally does not contain fat. In this report we describe an unusual case in which multiple areas of FNH were surrounded by prominent peripheral fatty infiltration.

The effect of amplitude-modulated (AM) noise on speech recognition in listeners with normal and impaired hearing was investigated in two experiments. In the first experiment nonsense syllables were presented in high-pass steady-state or AM noise to determine whether the release from masking in AM noise relative to steady-state noise was significantly different between normal-hearing and hearing-impaired subjects when the two groups listened under equivalent masker conditions. The normal-hearing subjects were tested in the experimental noise under two conditions: (a) in a spectrally shaped broadband noise that produced pure tone thresholds equivalent to those of the hearing-impaired subjects, and (b) without the spectrally shaped broadband noise. The release from masking in AM noise was significantly greater for the normal-hearing group than for either the hearing-impaired or masked normal-hearing groups. In the second experiment, normal-hearing and hearing-impaired subjects identified nonsense syllables in isolation and target words in sentences in steady-state or AM noise adjusted to approximate the spectral shape and gain of a hearing aid prescription. The release from masking was significantly less for the subjects with impaired hearing. These data suggest that hearing-impaired listeners obtain less release from masking in AM noise than do normal-hearing listeners even when both the speech and noise are presented at levels that are above threshold over much of the speech frequency range.

The purpose of this article is to provide an overall summary of the role probe insertion depth has on real ear measurements, and to compare the real ear sound pressure level measured by a probe microphone system, using three methods for positioning the probe in an ear canal. The probe insertion techniques that were compared included: (1) an acoustic method that incorporates use of the quarter-wave antiresonance property of the ear to determine acoustically the location of the probe tube relative to the eardrum in an individual ear; (2) a constant insertion depth method (25 mm from the intratragal notch); and (3) the earmold +5 mm method, which places the probe 5 mm beyond the tip of the individual's earmold in the canal, thereby avoiding problems associated with the transition region, where sound exits from the bore of the earmold into the larger ear canal. Measurements were obtained for each method at 32 frequencies in the unoccluded ears of 17 subjects. Results indicated that the sound pressure levels measured by the acoustic method were significantly larger than those measured by the other two methods. This result was most evident in subjects with long ear canals (> 25 mm) and at high test frequencies (4.0 to 6.3 kHz). For subjects with short or average length ear canals, the three methods provided essentially equivalent results.

The Wnt gene family in vertebrates comprises at least 11 distinct genes but the only family member previously identified in Drosophila has been the segment polarity gene wingless (wg), the ortholog of vertebrate Wnt-1. In this report we describe the isolation of a novel Drosophila Wnt gene, Dwnt-5, which differs significantly from wg in both the pattern of its expression during embryogenesis and the predicted structure of its product. Dwnt-5 encodes a polypeptide of 112 kDa, which is more than twice as large as the products of previously known Wnt genes. The protein shares homology with other Wnt sequences in its carboxy-terminal half only and is most closely related to the products of vertebrate Wnt-5a and Wnt-5b. Dwnt-5 is expressed in a complex pattern during Drosophila embryogenesis. At the extended germ band stage, however, transcripts accumulate specifically in the nascent limb primordia of the head and thoracic segments. We show that this elevated expression depends on the activity of the homeobox gene Distal-less (Dll) and suggest that the Dwnt-5 gene may constitute a downstream target of Dll that acts in the specification of these primordia.

Economic and social change in the developing countries of Asia, Africa, Latin America, and the Pacific Islands is associated with increased rates of behavior-related illnesses, including psychiatric disorders, alcoholism, and substance abuse. Between 10 and 20 percent of the presenting problems in primary care settings in those countries are psychosocial. The authors provide an overview of the epidemiology of psychiatric and psychosocial morbidity in developing countries and summarize its effect on medical care systems in those settings. They suggest that American psychiatry increase its involvement in improving mental health care in developing countries. Consultation should be directed toward priorities determined locally in those countries, including assessment of current clinical practices, applied epidemiologic research, and training of indigenous researchers.

The systematic, population-wide application of preventive measures based on what is known about the causes and outcomes of psychiatric disorders can markedly reduce morbidity from mental ill health among children in the Americas. The actions proposed here rely partly upon increasing access for all women and their children to thoroughly tested obstetric and pediatric care; in part they depend on improving nutrition and opportunities for cognitive stimulation; and in part they call for enhancing the mental health skills of primary care practitioners by appropriate in-service training. There are limits to our knowledge and to the effectiveness of some of our interventions; nonetheless, the greatest barrier to better child mental health is failure to muster the political will to apply what is known to the care of mothers and children in all sectors of society.

The epidemiology of AIDS reflects interactions among biological, psychological and social factors. The immune response to the infectious agent is relatively ineffectual; the course of the disease it produces is chronic. The long interval between HIV infection and the appearance of clinical disease maximizes "silent" transmission. The infection is transmitted behaviourally; that is, primarily via specific sexual acts and contaminated paraphernalia employed by IV drug users. The virus entered human populations in an era when such behaviours had become very much more prevalent in response to social change. The public health response to the epidemic was seriously compromised by the stigma attached to the persons victimized by the disease; thus, the mobilization of adequate resources was markedly delayed. Irrational fears of contamination led to proposals for mandatory population-wide screening, in utter disregard of the high false to true positive ratio in screening tests when prevalence is low. Welcome as a vaccine to prevent HIV infection would be, it is not likely to be available, if it can be produced at all, before the end of the century. Control of the epidemic demands that stigma be vigorously combated and that all groups of the population be educated about ways to minimize the likelihood of becoming infected and of transmitting the virus.

To evaluate the function of the murine ornithine decarboxylase (ODC) gene promoter, expression of chimeric ODC-chloramphenicol acetyltransferase (CAT) plasmids (pODCcat) containing 1,658 nt of the ODC promoter sequence and its various 5'-deletions was analyzed. In transient expression assays with NIH/3T3 mouse cells, pODCcat constructs exhibited fairly strong promoter activity yielding CAT values up to 40% of those obtained with the viral promoter RSV. Interestingly, 5'-deletions of the pODCcat constructs increased the promoter activity over that achieved using the entire 1.6-kb 5'-flanking region, with the highest activity being observed with about 750 nt of the ODC promoter. This finding suggests that the distal part of the promoter includes DNA elements which are involved in repressing its function. The promoter region could be deleted down to the proximal 97 nt and still be stimulated by cAMP to the same extent as the 1.6-kb promoter. DNase I footprinting and methylation interference studies showed that a specific protein binds to the region from -59 to -39, which encompasses a DNA motif resembling the consensus cyclic AMP response element (CRE). However, comparative gel retardation and Southwestern blotting experiments with the putative ODC-CRE and the somatostatin promoter CRE indicated that the 70-kDa protein interacting with the CRE-like element of the ODC promoter is different from the well-characterized nuclear CRE-binding protein CREB.

A two-microphone dereverberation technique was evaluated by obtaining speech recognition measures and preference judgments from normal-hearing and hearing-impaired listeners. Monaural speech recognition performance was measured for two reverberation conditions (0.4 second and 1.2 seconds) with and without processing. Binaural speech recognition performance was also measured for the unprocessed conditions. In addition, paired-comparison judgments of preference were obtained for all combinations of the processed and unprocessed monaural stimuli. For both groups of subjects, scores at the shorter reverberation time were significantly higher than scores for the longer reverberation time. For the normal-hearing subjects, processing to dereverberate had no significant effect on speech recognition performance. Binaural presentation of the unprocessed signal yielded significantly higher scores. For the hearing-impaired subjects, performance was significantly better in the unprocessed condition than the processed condition, but was not significantly different from the binaural condition. Paired-comparison judgments revealed differences in patterns of preference between normal-hearing and hearing-impaired listeners.

The purpose of this study was to assay the concentration of metronidazole in gingival fluid, to correlate clinical and microbiologic parameters of periodontal disease to each other and to the gingival fluid concentration of the drug. Ten subjects with a minimum of two contralateral pairs of periodontal pockets of greater than or equal to 5 mm were utilized. One side of the mouth was selected to serve as the root-planed site while the other was left untreated. On day 0, plaque and bleeding-time indexes and probing depths were recorded. Subgingival plaque was analyzed using phase contrast microscopy. When root planing was completed, the subjects were prescribed either metronidazole or placebo three times daily for seven days. Within 24 hours of the last dose, and thereafter at intervals of 1, 2 and 3 weeks, fluid samples were assayed for metronidazole. Clinical and bacterial data were likewise recorded. The results indicate that root planing with metronidazole appears to be more effective in promoting periodontal health than root planing alone. Concentrations of metronidazole ranging from 5 to 20 micrograms/ml were detectable in fluid samples obtained within 24 hours of administration of the last dose. No discernible levels could be found in samples taken at the longer intervals.

Ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC) are two key enzymes in polyamine biosynthesis. Both the ODC and the AdoMetDC gene is regulated by androgens in accessory sex organs of mice and rats, whereas only the ODC gene is androgen-responsive in rodent kidney. Androgenic responses in murine and rat kidneys are, however, dissimilar in that the induction of ODC activity and ODC mRNA accumulation is transient in the rat but sustained in the murine renal cells. In addition, in situ hybridization experiments with single-stranded cRNA probes revealed that ODC gene expression occurs in different subpopulations of epithelial cells of the proximal tubules in mice and rats. ODC and AdoMetDC genes are androgen-regulated in the same cell types of the accessory sex organs, as judged by hybridization histochemistry. Sequencing of the promotor region of the murine ODC gene has indicated the presence of several DNA elements for binding of transcription factors/regulatory proteins, including a putative androgen-response element at about 900 nucleotides upstream of the transcription start site.

Twenty-one infants less than 6 months of age with gastrointestinal symptoms of cow milk and/or soy protein-based infant formula intolerance (diarrhea in 14, hematochezia in 16, emesis in 8, failure to thrive in 4, and colic in 10) were treated clinically with a whey protein hydrolysate formula. Six patients improved when placed directly on the formula, and 15 remained asymptomatic or improved when given the whey hydrolysate formula following initial treatment with a casein hydrolysate or elemental formula. Eighteen had supporting evidence of an allergic basis for their symptoms, including a family history of allergies in 6, a clinical challenge with the offending formula in 1, laboratory tests consistent with atopy in 11, and/or rectal biopsy with histologic allergic features in 7. The whey hydrolysate formula may be an acceptable alternative to soy or casein hydrolysate formulas in most infants with gastrointestinal symptoms of cow milk and/or formula intolerance.

In vitro PFC responses to the thymus-independent (TI) antigen Streptococcus pneumoniae R36a require T cell replacing factor(s) (TRF). This requirement for TRF is as significant as for the thymus-dependent (TD) antigen SRBC. TRF is shown to be distinct from IL 2 by the following observations: 1) culture supernatants from the cloned T cell line L2, collected over an 8-day period after allogeneic stimulation, transiently contain IL 2 activity but maintain high levels of TRF activity throughout 192 hr; 2) L2V, a variant subclone of L2, produces much higher levels of TRF activity than the parental line but no detectable IL 2 activity; 3) the addition of IL2+, TRF- supernatants from the T cell hybridoma FS6-14.13 does not affect the L2V SF-driven PFC responses to R36a or SRBC; and 4) the addition of contaminating T cells to cultures containing T cell-depleted spleen cells, L2V SF, and antigen does not affect the PFC response. TRF does appear to be indistinguishable from polyclonal B cell stimulating factor (BCSF), which stimulates polyclonal PFC responses in the absence of antigen, mitogen, or anti-Ig. The TRF and BCSF activities of L2V SF could not be separated by ion-exchange, hydrophobic-interaction, and gel-filtration chromatography. TRF and BCSF have an apparent m.w. of approximately 40,000.

The transitions from person to patient and back represent social decision points rather than boundaries determined by shifting biological equilibria, as doctors so often suppose. Moreover, host resistance to pathogenic agents is weakened by social stress and strengthened by social support. Thus, the efficiency and effectivenss of medical care will be improved if the clinician, in assessing patient problems, systematically inquires into the social determinants of the decision to seek help. The probability of resolving the patient's difficulties will be enhanced by targeting treatment measures at the social components of the illness experience as well as at the pathophysiology of the disease process.

Contrary to the common assertion that there is too much science in medicine, it is precisely the application of the natural sciences in the clinic that has enhanced the diagnostic and therapeutic powers of the physician. Much of the criticism of science in medicine mistakes the technology made possible by science, and the way that technology is employed, for science itself. What has hampered progress is too narrow a view of the sciences relevant to medicine. The concepts and methods of the social sciences must be integrated into medical education if physicians are to be enabled to respond effectively to illness as a human experience. Nonetheless, without major changes in the social context of medical practice, efforts to improve performance through curriculum reform will be futile.

Different preventive approaches of mental and neurological disorders are discussed. Special emphasis has been put on the advances of biological research in the elucidation of aetiological and pathogenic mechanisms of major psychoses, such as schizophrenia and affective disorders. Perspectives of genetic and psychopharmacological research are emphasized. Multidisciplinary efforts are needed for the improvement of existing preventive measures.

We have examined regulatory domains of the human IL-2 gene promoter by transfection and transient expression of rDNA constructs in which the chloramphenicol acetyl transferase gene shows T cell-specific inducible expression and cyclosporin A-mediated inhibition when placed downstream of 587 bp of the human IL-2 5'-flanking region. A series of 5'-deletion constructs transfected into the Jurkat T lymphoid line demonstrates that a region encompassing 370 bp 5' of the transcription start site is sufficient for inducible chloramphenicol acetyl-transferase expression. Further dissection of this region with internal deletion (linker-scanner) mutants revealed that portions of at least two discrete regions from -42 to -169 and -289 to -361 bp relative to the transcription start site are critical for inducible expression of the IL-2 gene. T cell-specific expression of wild-type and mutant IL-2 promoter constructs could be increased severalfold by the insertion of an upstream SV40 enhancer. With use of a battery of IL-2 promoter constructs, we could not identify subregions within IL-2 5'-flanking sequences which are crucial for cyclosporin A inhibition of the IL-2 gene or deletion of which resulted in loss of T cell-specific expression, suggesting that such functions may be mediated at pre-transcriptional levels.

Tone decay was studied in a group of 17 profoundly deaf adults who have a single-channel cochlear implant. With direct electrical input through the subject's induction coil system, tone decay was evaluated at 125, 250, 500, 2 000, 4 000, and 16 000 Hz. Results indicated that as the intensity of electrical stimulation increased, the ability to perceive a continuous signal also increased for the majority of the subjects. All but 3 of the subjects were able to perceive the electrical signal at suprathresholds for 2 min. The 3 subjects who exhibited tone decay differed from the rest of the sample in several ways: (1) they became deaf at an earlier age; (2) they had more years of profound deafness, and (3) they had fewer years of cochlear implant and hearing aid use.

A direct correlation between the percentage of cells in S phase of the cell cycle and the clinical behavior of lymphocytic lymphomas of low, intermediate, and high grade malignancy has been described. The histopathologist has used the mitotic rate and other morphologic criteria such as size of cells and nuclear characteristics as predictors/indicators of the aggressiveness of a tumor. We compared the S phase values of 22 cases of poorly differentiated lymphocytic lymphoma (PDL) of the B cell type, using flow cytometric measurement of DNA content, to morphologic features and mitotic rate (MR). The 22 cases were divided into 3 histologic groups: nodular PDL composed of small, cleaved lymphocytes (11 cases); follicular mantle zone lymphoma and those of intermediate differentiation (6 cases); and "blastic" PDL (5 cases). In Group 1 there was excellent correlation of MR, percentage of cells in S phase, and proportion of large cells (transformed lymphocytes) per high power field (HPF). In Group 2, this correlation was not found between MR and percentage of cells in S phase in five of the six cases. The high S phase in this group did correlate with the large proportion of large cells found primarily in pseudofollicular proliferation centers and in remnants of true follicular centers. These cells may have a prolonged S phase and thus fewer mitoses were seen. In Group 3, although both MR and S phases were high, a direct correlation between them as noted in the Group 1 cases was not seen, but an excellent correlation of the high S phase and the number of blasts was present. The fact that three of the five patients in this group died rapidly (within less than 2 years of presentation) and the two survivors were experiencing rapid progression of disease, supports the concept that this group represents a clearly different, more aggressive subclass of PDL.

Many clinicians feel that single-channel cochlear implants are limited in the information they can provide. This has led to some common misconceptions regarding single-channel and multichannel systems. At the House Ear Institute, a growing number of children with the 3M/House single-channel implant are demonstrating open-set understanding of speech on measures designed to test such abilities in children. As a result, we have revised our thinking regarding the potential of this device.