PSYCHOTHERAPY OF ALCOHOLICS—The Concept of Psychotherapeutic Motivation

The psychiatric patient''s compliance with requirements of therapy (attendance, responsiveness, verbalization, etc.) often is adopted by the therapist as the chief criterion of motivation for cure. By these standards alcoholics often are judged to be poorly motivated and unsuited to the therapist''s mode of therapy. In such cases, the method may have to be adapted to the case, and a more permissive attitude taken toward the patient''s apparent noncooperation.     

MARRIAGE PROBLEMS—Dealing with Them in Private Practice

Marriages and divorces in Los Angeles County almost equal each other. Marriage per se is not the cause of neurosis. When two neurotic persons marry, the resulting neurotic interaction too often ends in conflict, broken homes and a new generation of neurotic children.Psychotherapy must be related to the diagnosis of family psychopathology, should include all the involved members and should be directed toward the realistic goal of integrating them into family living.Of 100 cases taken from the author''s experience, 64 involved married couples and the majority of these had serious interspouse conflicts. In 37 cases both spouses were treated and substantial psychotherapy was given to one or both of the partners. It included one or more modalities varying from electroshock therapy, tranquilizers, and such psychotherapy as supportive, dynamic interpretive, individual, spouses together, group and hypnotherapy. Thirteen achieved clinical recovery, nine improved, twelve were still in therapy. In three cases therapy failed.     

Cooperation in Health: Mapping Collaborative Networks on the Web

Objective

To map and investigate the relationships established on the web between leading health-research institutions around the world.

Methods

Sample selection was based on the World Health Organization (WHO) Collaborating Centres (CCs). Data on the 768 active CCs in 89 countries were retrieved from the WHO''s database. The final sample consisted of 190 institutions devoted to health sciences in 42 countries. Data on each institution''s website were retrieved using webometric techniques (interlinking), and an asymmetric matrix was generated for social network analysis.

Findings

The results showed that American and European institutions, such as the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH) and the National Institute of Health and Medical Research (INSERM), are the most highly connected on the web and have a higher capacity to attract hyperlinks. The Karolinska Institute (KI-SE) in Sweden is well placed as an articulation point between several integrants of the network and the component''s core but lacks general recognition on the web by hyperlinks. Regarding the north-south divide, Mexico and Brazil appear to be key southern players on the web. The results showed that the hyperlinks exchanged between northern and southern countries present an abysmal gap: 99.49% of the hyperlinks provided by the North are directed toward the North itself, in contrast to 0.51% that are directed toward the South. Regarding the South, its institutions are more connected to its northern partners, with 98.46% of its hyperlinks directed toward the North, and mainly toward the United States, compared with 1.54% toward southern neighbors.

Conclusion

It is advisable to strengthen integration policies on the web and to increase web networking through hyperlink exchange. In this way, the web could actually reflect international cooperation in health and help to legitimize and enhance the visibility of the many existing south-south collaboration networks.     

Potential therapeutic implications of new insights into respiratory syncytial virus disease

Viral bronchiolitis is the most common cause of hospitalization in infants under 6 months of age, and 70% of all cases of bronchiolitis are caused by respiratory syncytial virus (RSV). Early RSV infection is associated with respiratory problems such as asthma and wheezing later in life. RSV infection is usually spread by contaminated secretions and infects the upper then lower respiratory tracts. Infected cells release proinflammatory cytokines and chemokines, including IL-1, tumor necrosis factor-α, IL-6, and IL-8. These activate other cells and recruit inflammatory cells, including macrophages, neutrophils, eosinophils, and T lymphocytes, into the airway wall and surrounding tissues. The pattern of cytokine production by T lymphocytes can be biased toward 'T-helper-1' or 'T-helper-2' cytokines, depending on the local immunologic environment, infection history, and host genetics. T-helper-1 responses are generally efficient in antiviral defense, but young infants have an inherent bias toward T-helper-2 responses. The ideal intervention for RSV infection would be preventive, but the options are currently limited. Vaccines based on protein subunits, live attenuated strains of RSV, DNA vaccines, and synthetic peptides are being developed; passive antibody therapy is at present impractical in otherwise healthy children. Effective vaccines for use in neonates continue to be elusive but simply delaying infection beyond the first 6 months of life might reduce the delayed morbidity associated with infantile disease.     

Luteinizing hormone as a key player in the cognitive decline of Alzheimer's disease

This article is part of a Special Issue "SBN 2014".Alzheimer's disease is one of the most prevalent and costly neurological diseases in the world. Although decades of research have focused on understanding Alzheimer's disease pathology and progression, there is still a great lack of clinical treatments for those who suffer from it. One of the factors most commonly associated with the onset of Alzheimer's disease is a decrease in levels of gonadal hormones, such as estrogens and androgens. Despite the correlational and experimental data which support the role of these hormones in the etiology of Alzheimer's disease, clinical trials involving their reintroduction through hormone therapy have had varied results and these gonadal hormones often have accompanying health risks. More recently, investigation has turned toward other hormones in the hypothalamic–pituitary–gonadal axis that are disrupted by age-related decreases in gonadal hormones. Specifically, luteinizing hormone, which is increased with age in both men and women (in response to removal of negative feedback), has surfaced as a potentially powerful player in the risk and onset of Alzheimer's disease. Mounting evidence in basic research and epidemiological studies supports the role of elevated luteinizing hormone in exacerbating age-related cognitive decline in both males and females. This review summarizes the recent developments involving luteinizing hormone in increasing the cognitive deficits and molecular pathology characteristic of Alzheimer's disease.     

The Ubiquitin–Proteasome System in Retinal Health and Disease

The ubiquitin–proteasome system (UPS) is the main intracellular pathway for modulated protein turnover, playing an important role in the maintenance of cellular homeostasis. It also exerts a protein quality control through degradation of oxidized, mutant, denatured, or misfolded proteins and is involved in many biological processes where protein level regulation is necessary. This system allows the cell to modulate its protein expression pattern in response to changing physiological conditions and provides a critical protective role in health and disease. Impairments of UPS function in the central nervous system (CNS) underlie an increasing number of genetic and idiopathic diseases, many of which affect the retina. Current knowledge on the UPS composition and function in this tissue, however, is scarce and dispersed. This review focuses on UPS elements reported in the retina, including ubiquitinating and deubiquitinating enzymes (DUBs), and alternative proteasome assemblies. Known and inferred roles of protein ubiquitination, and of the related, SUMO conjugation (SUMOylation) process, in normal retinal development and adult homeostasis are addressed, including modulation of the visual cycle and response to retinal stress and injury. Additionally, the relationship between UPS dysfunction and human neurodegenerative disorders affecting the retina, including Alzheimer's, Parkinson's, and Huntington's diseases, are dealt with, together with numerous instances of retina-specific illnesses with UPS involvement, such as retinitis pigmentosa, macular degenerations, glaucoma, diabetic retinopathy (DR), and aging-related impairments. This information, though still basic and limited, constitutes a suitable framework to be expanded in incoming years and should prove orientative toward future therapy design targeting sight-affecting diseases with a UPS underlying basis.     

Management of refractory and complicated reflux esophagitis.

Simple intermittent heartburn with minor or no esophagitis can be treated with simple measures including lifestyle changes and antacids as needed, or H2 receptor antagonists (H2RA), and has a good outcome. Problematic reflux includes resistance to therapy, stricture, Barrett''s esophagus and aspiration. Severe reflux esophagitis, often resistant to H2RA therapy, requires more potent treatment with potent acid suppression using proton pump inhibitors, often indefinitely. When complicated by stricture, dilatations with potent acid suppression are needed. Barrett''s esophagus is subject to esophagitis, which is no more difficult to treat than other cases of esophagitis. Reflux in Barrett''s esophagus should be treated on its own merits without regard to the presence of Barrett''s epithelium. Dysplasia leading to adenocarcinoma is a different problem, apparently not influenced by reduced exposure to acid. Indications for antireflux surgery are quite limited and should be carefully analyzed as a cost/risk/benefit problem.     

Subspecialty Differences in Responding to Patient Death–Comparing Cardiologists With Oncologists

Cardiac deaths are more likely to be unanticipated than cancer deaths by patients, their families, and their physicians. We hypothesized that differing physician attitudes toward dying patients may affect the degree of expectation of death. To evaluate differences in attitudes and behaviors among subspecialists, we surveyed a randomly selected population of California subspecialists; 44 of 136 (32%) of cardiologists and 91 of 167 (55%) of oncologists responded. Oncologists experienced three times as many deaths as cardiologists and reported having discussed code status more often with patients who died. Cardiologists'' patients'' deaths were more often unexpected and occurred more frequently in intensive care units. In addition, their patients were more likely to be given cardiopulmonary resuscitation. Oncologists reported being more comfortable dealing with dying patients and having less desire to avoid them. When presented with patient scenarios, however, cardiologists'' and oncologists'' responses were similar when discussing and estimating prognosis and likelihood of successful therapy.     

Mental Health: The Search for a Definition

Various attempts to define the concept of “mental health” are examined. Value judgments permeate much mental health literature. Their use militates against obtaining an objective definition, capable of universal application. The acceptance of a definition including a value judgment implies taking an attitude toward a particular society and its social ideals.Present limits of competence only allow us to describe “mental health” conceptually. Such “untechnical” proposals are liable to be confused with “technical” (“scientific”) propositions. Multiple criteria are likely to be helpful in improving our concept of “mental health”.The intrusion of morals into the world of health is discussed as part of the contemporary intellectual dilemma of determined human behaviour versus human responsibility and the reality of moral values.It is suggested that “mental health” might consist simply of an individual''s possession of insight into his own personality, combined with an honest recognition and acceptance of his condition.     

Phosphorylation of Synaptic GTPase-activating Protein (synGAP) by Ca2+/Calmodulin-dependent Protein Kinase II (CaMKII) and Cyclin-dependent Kinase 5 (CDK5) Alters the Ratio of Its GAP Activity toward Ras and Rap GTPases

synGAP is a neuron-specific Ras and Rap GTPase-activating protein (GAP) found in high concentrations in the postsynaptic density (PSD) fraction from the mammalian forebrain. We have previously shown that, in situ in the PSD fraction or in recombinant form in Sf9 cell membranes, synGAP is phosphorylated by Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), another prominent component of the PSD. Here, we show that recombinant synGAP (r-synGAP), lacking 102 residues at the N terminus, can be purified in soluble form and is phosphorylated by cyclin-dependent kinase 5 (CDK5) as well as by CaMKII. Phosphorylation of r-synGAP by CaMKII increases its HRas GAP activity by 25% and its Rap1 GAP activity by 76%. Conversely, phosphorylation by CDK5 increases r-synGAP''s HRas GAP activity by 98% and its Rap1 GAP activity by 20%. Thus, phosphorylation by both kinases increases synGAP activity; CaMKII shifts the relative GAP activity toward inactivation of Rap1, and CDK5 shifts the relative activity toward inactivation of HRas. GAP activity toward Rap2 is not altered by phosphorylation by either kinase. CDK5 phosphorylates synGAP primarily at two sites, Ser-773 and Ser-802. Phosphorylation at Ser-773 inhibits r-synGAP activity, and phosphorylation at Ser-802 increases it. However, the net effect of concurrent phosphorylation of both sites, Ser-773 and Ser-802, is an increase in GAP activity. synGAP is phosphorylated at Ser-773 and Ser-802 in the PSD fraction, and its phosphorylation by CDK5 and CaMKII is differentially regulated by activation of NMDA-type glutamate receptors in cultured neurons.     

THE VISIBILITY OF MONOCHROMATIC RADIATION AND THE ABSORPTION SPECTRUM OF VISUAL PURPLE

1. After a consideration of the existing data and of the sources of error involved, an arrangement of apparatus, free from these errors, is described for measuring the relative energy necessary in different portions of the spectrum in order to produce a colorless sensation in the eye. 2. Following certain reasoning, it is shown that the reciprocal of this relative energy at any wave-length is proportional to the absorption coefficient of a sensitive substance in the eye. The absorption spectrum of this substance is then mapped out. 3. The curve representing the visibility of the spectrum at very low intensities has exactly the same shape as that for the visibility at high intensities involving color vision. The only difference between them is their position in the spectrum, that at high intensities being 48 µµ farther toward the red. 4. The possibility is considered that the sensitive substances responsible for the two visibility curves are identical, and reasons are developed for the failure to demonstrate optically the presence of a colored substance in the cones. The shift of the high intensity visibility curve toward the red is explained in terms of Kundt''s rule for the progressive shift of the absorption maximum of a substance in solvents of increasing refractive index and density. 5. Assuming Kundt''s rule, it is deduced that the absorption spectrum of visual purple as measured directly in water solution should not coincide with its position in the rods, because of the greater density and refractive index of the rods. It is then shown that, measured by the position of the visibility curve at low intensities, this shift toward the red actually occurs, and is about 7 or 8 µµ in extent. Examination of the older data consistently confirms this difference of position between the curves representing visibility at low intensities and those representing the absorption spectrum of visual purple in water solution. 6. It is therefore held as a possible hypothesis, capable of direct, experimental verification, that the same substance—visual purple—whose absorption maximum in water solution is at 503 µµ, is dissolved in the rods where its absorption maximum is at 511 µµ, and in the cones where its maximum is at 554 µµ (or at 540 µµ, if macular absorption is taken into account, as indeed it must be).     

Quetzal Abundance in Relation to Fruit Availability in a Cloud Forest in Southeastern Mexico1

The Resplendent Quetzal (Pharomachrus mocinno) is an altitudinal migrant that nests in high elevation cloud forests and migrates toward lower areas during the summer rainy season. It has been suggested that its migratory movements are related to the abundance of ripe Lauraceae fruits. We studied the quetzal diet during two consecutive years, as well as changes in fruit abundance of the plant species on which the bird feeds at El Triunfo Biosphere Reserve, southeastern Mexico. The quetzal was observed feeding on 32 plant species; of these, 24 are new records in its diet. We chose 20 of these 32 species and studied their fruit phenology for two years in order to describe the relationship between fruit and quetzal abundance. Our results showed that quetzal abundance in the breeding area was correlated with the total number of fruiting species, whereas the correlation between quetzal abundance and the number of fruiting Lauraceae species was only marginal. Additionally, a correlation test showed that quetzal abundance was marginally correlated with total fruit availability (total no. of fruits per month); however, the correlation between quetzal abundance and the number of fruits in the Lauraceae was not significant. Our results suggest that the dynamics of food resources may be playing a major role in the quetzal's migratory behavior. Knowing the bird's diet may aid in characterizing the type of habitat adequate for its conservation. Our observations in this respect suggest that conservation efforts to preserve this bird species should concentrate on the protection of its habitat, including both breeding and nonbreeding (migration) locations.     

Inhibition of neuronal nitric oxide synthase activity promotes migration of human‐induced pluripotent stem cell‐derived neural stem cells toward cancer cells

The breakthrough in derivation of human‐induced pluripotent stem cells (hiPSCs) provides an approach that may help overcome ethical and allergenic challenges posed in numerous medical applications involving human cells, including neural stem/progenitor cells (NSCs). Considering the great potential of NSCs in targeted cancer gene therapy, we investigated in this study the tumor tropism of hiPSC‐derived NSCs and attempted to enhance the tropism by manipulation of biological activities of proteins that are involved in regulating the migration of NSCs toward cancer cells. We first demonstrated that hiPSC‐NSCs displayed tropism for both glioblastoma cells and breast cancer cells in vitro and in vivo. We then compared gene expression profiles between migratory and non‐migratory hiPSC‐NSCs toward these cancer cells and observed that the gene encoding neuronal nitric oxide synthase (nNOS) was down‐regulated in migratory hiPSC‐NSCs. Using nNOS inhibitors and nNOS siRNAs, we demonstrated that this protein is a relevant regulator in controlling migration of hiPSC‐NSCs toward cancer cells, and that inhibition of its activity or down‐regulation of its expression can sensitize poorly migratory NSCs and be used to improve their tumor tropism. These findings suggest a novel application of nNOS inhibitors in neural stem cell‐mediated cancer therapy.     

L-DOPA-induced hyperhomocysteinemia in Parkinson's disease: Elephant in the room

BackgroundDopamine replacement therapy by its precursor, L-3.4-dihydroxyphenylalanine (L-DOPA), has been the treatment of choice for Parkinson's disease. However, the possible contributory effect of L-DOPA therapy on the progression of Parkinson's disease mediated by the L-DOPA-induced toxic metabolites remains elusive.Scope of reviewProlong use of L-DOPA leads to behavioral impediments and instigate the generation of several toxic metabolites. One such metabolite is homocysteine, the level of which increases in the plasma of Parkinson's disease patients undergoing L-DOPA therapy, as well as in brain of animal models of the disease. In concoction with parkinsonian neurotoxins, Hcy exaggerates dopaminergic neurodegeneration, while its intranigral infusion has been demonstrated to decrease the dopamine level as well as causes dopaminergic neurodegeneration. Therefore, it can be propounded that elevated level of Hcy (hyperhomocysteinemia) is one of the underlying causes of L-DOPA-induced side-effects and aggravates the progressive nature of Parkinson's disease, which has been focused here. We have provided a conjectural discussion on the involvement of Hcy in L-DOPA-induced dyskinesia in Parkinson's disease.ConclusionHyperhomocysteinemia as a result of prolonged L-DOPA therapy is the emerging cause of L-DOPA-induced behavioral abnormalities and progressive nature of Parkinson's disease.General significanceThis review highlights that hyperhomocysteinemia could be a putative contributor of the side-effects of chronic L-DOPA therapy because of its neurotoxic potency.     

Replacement of an interdomain residue Val39 of Escherichia coli aspartate aminotransferase affects the catalytic competence without altering the substrate specificity of the enzyme

Three mutant Escherichia coli aspartate aminotransferases in which Val39 was changed to Ala, Leu, and Phe by site-directed mutagenesis were prepared and characterized. Among the three mutant and the wild-type enzymes, the Leu39 enzyme had the lowest Km values for dicarboxylic substrates. The Km values of the Ala39 enzyme for dicarboxylates were essentially the same as those of the wild-type (Val39) enzyme. These two mutant enzymes showed essentially the same kcat values for dicarboxylic substrates as did the wild-type enzyme. On the other hand, incorporation of a bulky side-chain at position 39 (Phe39 enzyme) decreased both the affinity (1/Km) and catalytic ability (kcat) toward dicarboxylic substrates. These results show that the position 39 residue is involved in the modulation of both the binding of dicarboxylic substrates to enzyme and the catalytic ability of the enzyme. Although the replacement of Val39 with other residues altered both the kcat and Km values toward various substrates including dicarboxylic and aromatic amino acids and the corresponding oxo acids, it did not alter the ratio of the kcat/Km value of the enzyme toward a dicarboxylic substrate to that for an aromatic substrate. The affinity for aromatic substrates was not affected by changing the residue at position 39. These data indicate that, although the side chain bulkiness of the residue at position 39 correlates well with the activity toward aromatic substrates in the sequence alignment of several aminotransferases [Seville, M., Vincent M.G., & Hahn, K. (1988) Biochemistry 27, 8344-8349], the residue does not seem to be involved in the recognition of aromatic substrates.     

Modulation of synaptic plasticity by brain estrogen in the hippocampus

The hippocampus is a center for learning and memory as well as a target of Alzheimer's disease in aged humans. Synaptic modulation by estrogen is essential to understand the molecular mechanisms of estrogen replacement therapy. Because the local synthesis of estrogen occurs in the hippocampus of both sexes, in addition to the estrogen supply from the gonads, its functions are attracting much attention.     

Binding and internalization of 125I thrombin in chick embryo fibroblasts: Possible role in mitogenesis

Human α thrombin acts as a mitogen for cultures of resting chick embryo fibroblasts (CEF) in serum free medium. The use of ¹²⁵I-labeled thrombin shows that thrombin specifically binds to CEF and that after a lag of approximately 30 to 60 minutes it can not be removed by subsequent exposure to trypsin. The entry of ¹²⁵I thrombin into the trypsin-insensitive domain is not inhibited to any great extent by excess unlabelled thrombin. The cell-associated thrombin retains its native molecular weight and its catalytic activity toward synthetic amide substrates. It appears to be located in the crude nuclear fraction of homogenized CEF cells. The association of thrombin with CEF is specific, since the non-mitogenic serine protease chymotrypsin is internalized to a much lesser extent than thrombin. The data are discussed in terms of a possible intracellular site for thrombin's mitogenic action.     

Ethnic heterogamy and the risk of partner violence in Mexico

A common stereotype holds that in Mexico male violence toward women is common among indigenous peoples and reflects cultural norms that sanction a male's domination of his female partner. We employ a recent Mexican survey to examine the relative risk of violence against women as a function of the couple's ethnic homogamy. Among couples in which both partners are either non-indigenous or indigenous the female's risk of partner violence is similar. Among heterogamous couples non-indigenous females in relationships in which the male is indigenous are at elevated risk of violence, while indigenous women in relationships with non-indigenous males are at a lower risk of violence. The stresses associated with heterogamy appear to be more salient in determining a woman's risk of violence than ethnicity per se. The implications for future research and the need to deal with the issue of ethnic homogamy in culturally heterogeneous populations are discussed.     

Atg39 links and deforms the outer and inner nuclear membranes in selective autophagy of the nucleus

In selective autophagy of the nucleus (hereafter nucleophagy), nucleus-derived double-membrane vesicles (NDVs) are formed, sequestered within autophagosomes, and delivered to lysosomes or vacuoles for degradation. In Saccharomyces cerevisiae, the nuclear envelope (NE) protein Atg39 acts as a nucleophagy receptor, which interacts with Atg8 to target NDVs to the forming autophagosomal membranes. In this study, we revealed that Atg39 is anchored to the outer nuclear membrane via its transmembrane domain and also associated with the inner nuclear membrane via membrane-binding amphipathic helices (APHs) in its perinuclear space region, thereby linking these membranes. We also revealed that autophagosome formation-coupled Atg39 crowding causes the NE to protrude toward the cytoplasm, and the tips of the protrusions are pinched off to generate NDVs. The APHs of Atg39 are crucial for Atg39 crowding in the NE and subsequent NE protrusion. These findings suggest that the nucleophagy receptor Atg39 plays pivotal roles in NE deformation during the generation of NDVs to be degraded by nucleophagy.