[Social psychiatry and neurobiology : A long overdue convergence exemplified by schizophrenia]. / Sozialpsychiatrie und Neurobiologie : Eine längst fällige Annäherung am Beispiel der Schizophrenie.

BACKGROUND: The proliferation of biological psychiatry has greatly increased over the last two decades. With the possibility to carry out brain research using modern technical methods, it seemed that social influencing factors would lose importance in the development of mental diseases; however, in actual fact this does not seem to be justified. It is necessary to overcome this separation, in that social factors are incorporated into a conceptual framework in the development of mental diseases, which simultaneously also takes the results of current neurobiological research into consideration. OBJECTIVES AND METHODS: The aims of this review article are to summarize the current state of sociopsychiatric research and to emphasize the perspectives of the biological principles and their validity with respect to the social dimensions of psychiatry, as exemplified by schizophrenic disorders. The article presents the options for a biosocial approach in social psychiatry and gives an overview of the currently available literature. RESULTS AND CONCLUSION: There is an abundance of neurobiological research approaches, which are closely associated with sociopsychiatric topics, such as social cognition. Social psychiatry and biological psychiatry should no longer be considered as diametrically opposed subdisciplines. On the contrary, the options which could emerge from a synthesis must be used in research and clinical practice.

Relationship between personality and psychopathology in a longitudinal community study: a test of the predisposition model.

BACKGROUND: Mounting evidence supports the notion that personality is crucial in the aetiopathology of common mental disorders, but studies that allow for aetiological conclusions are lacking. The aim of the present study was thus to provide a test of the predisposition model. METHOD: We analysed data from the Zurich Cohort Study, a 30-year longitudinal epidemiological community study of an adult cohort (n = 591) from 1979 to 2008. Personality was assessed in 1988 with an established personality questionnaire, and psychopathology through seven semi-structured interviews between 1979 and 2008. RESULTS: On the basis of personality assessment from 1988, used as predictor of subsequent psychopathology (1993-2008), while adjusting for sex and prior mental disorders (1979-1988), neuroticism related significantly with future major depression episodes [odds ratio (OR) = 1.41], anxiety disorders (OR = 1.32) and depression treatment use (OR = 1.41). When participants with a past 10-year history (i.e. 1979-1988) of either major depression, anxiety disorder or depression treatment use were excluded, neuroticism in 1988 still significantly predicted first incidence (i.e. 1993-2008) of major depression episodes (OR = 1.53) and depression treatment use (OR = 1.84). CONCLUSIONS: The present study provides compelling evidence that the personality trait of neuroticism constitutes an independent risk factor for subsequent major depression episodes and use of respective professional treatments, which serves as a proxy for particularly severe and impairing depression episodes. We therefore advocate that personality traits could provide clinically useful prognostic information when considered carefully.

Changes in neurocognitive functioning during transition to manifest disease: comparison of individuals at risk for schizophrenic and bipolar affective psychoses.

BACKGROUND: Neurocognitive deficits are important aspects of schizophrenic disorder because they have a strong impact on social and vocational outcomes. Previously it was assumed that cognitive abilities progressively deteriorate with illness onset. However, recent research results have contradicted this with observations of continuous or even improved performance in individuals at risk for psychosis or manifest schizophrenia. The objective of our longitudinal study was to examine neurocognitive functioning in help-seeking individuals meeting basic symptoms or ultra-high-risk criteria for schizophrenic psychosis (HRSchiz) or risk criteria for affective psychosis (HRBip). The progression of cognitive functioning in individuals converting to psychosis was compared with that of at-risk individuals who did not convert during the follow-up period. METHOD: Data were available from 86 study participants who completed neurocognitive and clinical assessments at baseline and, on average, 12.8 (s.d. = 1.5) months later. Neurocognitive measures were grouped according to their load in factor analysis to five cognitive domains: speed, attention, fluency, learning and memory, and working memory. RESULTS: Neurocognitive functioning in HRSchiz and HRBip individuals generally improved over time. Subjects converting to manifest psychosis displayed a stable neurocognitive profile from baseline to follow-up. Compared with non-converters, they had already demonstrated a significantly lower level of performance during their baseline examinations. CONCLUSIONS: Our data provide no evidence for a progressive cognitive decline in individuals at risk of psychosis. In line with the neurodevelopmental model, our findings suggest that cognitive deficits are already present very early, before or during the prodromal stage of the illness.

Spatiotemporal properties of auditory intensity processing in multisensor MEG.

Loudness dependence of auditory evoked potentials (LDAEP) evaluates loudness processing in the human auditory system and is often altered in patients with psychiatric disorders. Previous research has suggested that this measure may be used as an indicator of the central serotonergic system through the highly serotonergic innervation of the auditory cortex. However, differences among the commonly used analysis approaches (such as source analysis and single electrode estimation) may lead to different results. Putatively due to discrepancies of the underlying structures being measured. Therefore, it is important to learn more about how and where in the brain loudness variation is processed. We conducted a detailed investigation of the LDAEP generators and their temporal dynamics by means of multichannel magnetoencephalography (MEG). Evoked responses to brief tones of five different intensities were recorded from 19 healthy participants. We used magnetic field tomography in order to appropriately localize superficial as well as deep source generators of which we conducted a time series analysis. The results showed that apart from the auditory cortex other cortical sources exhibited activation during the N1/P2 time window. Analysis of time courses in the regions of interest revealed a sequential cortical activation from primary sensory areas, particularly the auditory and somatosensory cortex to posterior cingulate cortex (PCC) and to premotor cortex (PMC). The additional activation within the PCC and PMC has implications on the analysis approaches used in LDAEP research.

Neurocognitive profiles in help-seeking individuals: comparison of risk for psychosis and bipolar disorder criteria.

BACKGROUND: Neurocognitive deficits are important aspects of the schizophrenic disorders because they have a strong impact on social and vocational outcomes. We expanded on previous research by focusing on the neurocognitive profiles of persons at high risk (HR) or ultra-high risk (UHR) for schizophrenic and affective psychoses. Our main aim was to determine whether neurocognitive measures are sufficiently sensitive to predict a group affiliation based on deficits in functional domains. METHOD: This study included 207 help-seeking individuals identified as HR (n = 75), UHR (n = 102) or at high risk for bipolar disorder (HRBip; n = 30), who were compared with persons comprising a matched, healthy control group (CG; n = 50). Neuropsychological variables were sorted according to their load in a factor analysis and were compared among groups. In addition, the likelihood of group membership was estimated using logistic regression analyses. RESULTS: The performance of HR and HRBip participants was comparable, and intermediate between the controls and UHR. The domain of processing speed was most sensitive in discriminating HR and UHR [odds ratio (OR) 0.48, 95% confidence interval (CI) 0.28-0.78, p = 0.004] whereas learning and memory deficits predicted a conversion to schizophrenic psychosis (OR 0.47, 95% CI 0.25-0.87, p = 0.01). CONCLUSIONS: Performances on neurocognitive tests differed among our three at-risk groups and may therefore be useful in predicting psychosis. Overall, cognition had a profound effect on the extent of general functioning and satisfaction with life for subjects at risk of psychosis. Thus, this factor should become a treatment target in itself.

Potassium restores vasorelaxation of resistance arterioles in non-hypertensive DOCA/salt fed mice.

BACKGROUND: Potassium-enriched diets exert renal and cardiovascular protective effects, but the underlying mechanisms are largely unknown. METHODS: Using the dorsal skinfold chamber model for intravital microscopy, we examined endothelium-dependent vasorelaxation of precapillary resistance arterioles in response to acetylcholine or the NO donor SNAP in awake mice. Experiments were performed in uni-nephrectomized one renin gene (Ren-1c) C57BL/6 mice (control group) and in mice having received a continuous administration of deoxycorticosterone acetate and a dietary supplementation of 1% sodium chloride for 8 weeks (DOCA/salt group). An additional group of DOCA/salt treated animals received a dietary supplement of 0.4% KCl for 3 weeks prior to the experiments (DOCA/salt + potassium group). RESULTS: DOCA/salt treatment for 8 weeks resulted in hypokalemia, but blood pressure remained unchanged. In DOCA/salt mice, relaxation of resistance arterioles was blunted in response to acetylcholine, and to a lesser extent to SNAP, suggesting endothelial dysfunction. Endothelium-dependent vasorelaxation was restored by the potassium-enriched diet. CONCLUSION: This study is the first to demonstrate a protective effect of potassium on endothelium-dependent vasorelaxation in the absence of confounding anti-hypertensive effects, as observed in most animal models and the clinical situation. We propose that the known cardio- and nephro-protective effects of potassium might - at least in part - be mediated by the salutary effects on endothelium-dependent arteriolar relaxation.

Fatty acids synthesized by oral treponemes in chemically defined media.

OMIZ-W68, a chemically defined medium that contains no long-chain fatty acids and yet supports in vitro proliferation of a wide range of fastidious oral anaerobes, is described. The type strains of Treponema denticola, Treponema lecithinolyticum, Treponema maltophilum, Treponema pectinovorum, Treponema socranskii, and an as yet unpublished canine Treponema species could be propagated indefinitely in this medium with sugar supplements for the saccharolytic species. Analysis of the cellular fatty acids (CFA) of these treponemes by gas chromatography demonstrated the synthesis of C14, C15, C16, and C17 fatty acids (linear-, iso-, and anteiso-forms) in various proportions, but neither hydroxy- nor unsaturated fatty acids. However, between 0% and 40% of the eluted material could not be identified. The proportions of CFAs differed not only between species but also between the eight strains of Treponema denticola investigated. Replacing OMIZ-W68 by a derivative minimal essential medium (OMIZ-M/TDCDK) developed for Treponema denticola had little effect on the CFA profiles. In contrast, the CFA profiles of treponemes grown in OMIZ-W68 showed at best minor similarity to the strains from the Moore library of the Virginia Polytechnic Institute, which had been grown in media containing serum, peptones, and yeast extract.

Actin III and myofilaments in different muscles of wildtype and the mutant raised of Drosophila melanogaster.

The mutation raised (rsd, 3-95.4) of Drosophila melanogaster causes flightlessness as a consequence of abnormalities in the fibrillar flight muscles (FFMs). In this muscle type actin III is neither synthesized nor accumulated while adult tubular muscles of rsd flies are indistinguishable from wildtype. This paper demonstrates ultrastructural defects in rds FFMs and extends the biochemical comparison of adult wildtype and rsd muscles to larval muscles and to embryo cells differentiating in culture. The FFMs of mature rsd flies contain thick filaments in irregular bundles, but no thin filaments. Normal Z-discs are virtually absent. Instead, a large number of Z-disc residues are present in stacks attached to short filaments on either side. In newly emerged rsd flies the disorganization is less pronounced. The adult tubular muscles and the supercontracting muscles of third-instar larvae of rsd can ultrastructurally not be distinguished from wildtype. The present biochemical results indicate that not only FFMs of mature and newly emerged adults are affected by the rsd genotype. Synthesis of actin III is not detectable in rsd FFMs which corresponds to the heavy structural defects. In addition to the lack of actin III synthesis in rsd FFMs, three unidentified proteins (52 kDa, 80 kDa, 90 kDa) which are specific for wildtype FFMs are also not synthesized in rsd flies. Among all other muscle types studied, all of which are morphologically unaffected, only adult tubular muscle of rsd genotype showed no biochemical effect. Larval supercontracting muscle as well as embryo cells differentiating in culture failed to synthesize actin III in the case of rsd cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of acute hemorrhage on transcutaneous, subcutaneous, intramuscular, and arterial oxygen tensions.

Although transcutaneous PO2 is a close approximation of arterial PO2 in most neonates, infants in shock often show lower transcutaneous than arterial PO2 values. For a better understanding of this discrepancy, we investigated the effect of acute hemorrhage on transcutaneous, tissue, and arterial PO2 in rabbits. With progressive hemorrhage, transcutaneous and tissue PO2 values declined steeply while arterial PO2 values did not. We speculate that the progressive decrement in transcutaneous and tissue PO2 value with hemorrhage is produced by diminished peripheral blood flow. Rather than representing a failure of the transcutaneous PO2 monitoring method, we speculate that transcutaneous hypoxia with shock may be a clinically valuable danger signal.

Transcutaneous oxygen tension measurements on limbs of diabetic and nondiabetic patients with peripheral vascular disease.

We measured transcutaneous oxygen tension (TcPo2) at a skin temperature of 44 degrees C on 319 limbs in an approximately equal number of nondiabetic and diabetic patients with peripheral vascular disease. Measurements were made above the knee, below the knee (BK), and on the dorsum of the foot. Nondiabetic limbs with leg/foot (the lesser of BK or foot) TcPo2 values below 20 mm Hg were significantly more likely to have ulcers, to have rest pain, or to require an amputation on the limb as compared with limbs with leg/foot TcPo2 values above 20 mm Hg. Patients with more severe symptoms had significantly reduced limb TcPo2 values, and these values were lower at more distal measurement sites. Generally, these results were similar in diabetic and nondiabetic patients without limb ulceration; however, the diabetic patients were more likely to have ulcers in the presence of high limb TcPo2. This observation suggests that ulceration in a substantial proportion of the diabetic patients may have resulted from factors other than insufficient cutaneous tissue oxygen delivery.

Relationship between transcutaneous oxygen tension, ankle blood pressure, and clinical outcome of vascular surgery in diabetic and nondiabetic patients.

We measured ankle systolic blood pressure (ABP) and limb transcutaneous oxygen tension (TcPO2) before and after 53 vascular procedures performed to relieve limb-threatening ischemia. We compared changes in ABP and TcPO2 and also compared these measurements of limb hemodynamics with the clinical outcome of the vascular procedures. For the procedures performed on patients without diabetes, both ABP and TcPO2 registered similar changes after surgery. Furthermore, those nondiabetic patients who had a postoperative ABP greater than 75 mm Hg or TcPO2 greater than 20 mm Hg showed resolution of the clinical symptoms within 60 days after surgery. All patients falling below these levels underwent a subsequent limb amputation. The results differed somewhat for procedures performed on patients with diabetes. First, a number of diabetic patients showed high ABP in conjunction with low TcPO2. We attribute these observations to the high incidence in diabetic patients of calcific medial stenosis leading to artificially elevated ABP measurements. Second, the clinical outcome among diabetic patients was uncorrelated with the postoperative ABP and was poorly correlated with postoperative TcPO2. Those diabetic patients with postoperative TcPO2 below 20 mm Hg showed unfavorable clinical outcomes, but many patients with postoperative TcPO2 greater than 20 mm Hg and postoperative ABP greater than 75 mm Hg also showed unfavorable clinical outcome (slow healing of ulcers, persistence of rest pain, and/or an amputation on the limb). These data suggest that among our patients with diabetes, simple relief of limb ischemia was not sufficient to result in a trouble-free clinical course. We conclude that TcPO2 is a useful replacement or adjunct to ABP measurements for evaluating the hemodynamic outcome of vascular surgery. Our results also suggest that it is extremely important to evaluate the outcome of such surgeries separately in patients with and without diabetes.

Factors relating to the sensory acuity of limbs with peripheral vascular insufficiency.

We examined several possible causes for the high incidence of poor sensory acuity in the limbs of 176 patients with moderate to severe peripheral vascular insufficiency. We investigated the relationships of diabetes, alcoholism, and smoking, as well as the severity of peripheral vascular disease, to the integrity of basic sensory modalities such as two-point discrimination and perception of light touch. The presence or absence of diabetes exerted the strongest effect on peripheral sensation. In patients who did not have diabetes, sensation in the limbs was most strongly affected by whether the patient was an alcoholic. Smoking did not have a significant effect on limb sensation. Among nondiabetic, nonalcoholic patients, there was a weak residual effect related to the severity of the peripheral vascular insufficiency. Even among these patients, however, systemic factors predominated in determining the loss of sensation. We also examined the extent to which loss of sensation might be related to the development of ulcers. Among patients who were not diabetic, there was a highly significant relationship between loss of sensation and the presence of limb ulceration. Surprisingly, however, there was no discernable relationship between the presence of ulcers in diabetic patients and the degree of loss of peripheral sensation. This result suggests that a large percentage of ulcers seen in diabetic patients are not of neurogenic origin.

Aspartame as a source of essential phenylalanine for the growth of oral anaerobes.

Phenylalanine and aspartic acid requirements were determined for 13 species of oral bacteria using the chemically defined medium OMIZ-W1. None of Actinobacillus actinomycetemcomitans, Bacteroides forsythus, Eikenella corrodens, Selenomonas sputigena, Treponema pectinovorum, T. socranskii, or Wolinella recta required either of these amino acid constituents of aspartame (L-aspartyl-L-phenylalanine methylester). Phenylalanine was essential for the growth of Capnocytophaga gingivalis, Eubacterium timidum, Fusobacterium nucleatum, Porphyromonas gingivalis, T. denticola, and T. vincentii, while aspartic acid was not required. With the exception of E. timidum, all phenylalanine-dependent strains could grow when the free amino acid was replaced by aspartame at concentrations at least 10-fold lower than those used for aspartame as an artificial sweetener.

Circulatory and mechanical response of skin to loading.

We investigated the tolerance of skin to mechanical loading over the tibia and over the tibialis anterior muscle in 12 normal volunteers. Surface load, subcutaneous tissue pressure, skin deformation under load, and transcutaneous partial pressure of oxygen (TcPO2) were simultaneously monitored. The skin over bone showed a significantly stiffer load deformation relationship than the skin over muscle (p less than 0.001). The displacement required to reduce TcPO2 to 0 over bone, 1.1 +/- 0.3 mm (mean +/- standard deviation), was significantly less than that required over tibialis anterior muscle, 5.4 +/- 1.1 mm (p less than 0.001). The applied pressure required to reduce TcPO2 to 0 was significantly greater for skin over muscle (71 +/- 16 mm Hg) than for skin over bone (42 +/- 8 mm Hg) (p less than 0.001). However, the subcutaneous pressure required to reduce TcPO2 to 0 was not significantly different for skin over muscle (36 +/- 11 mm Hg) than for skin over bone (28 +/- 10 mm Hg) (p greater than 0.05). Our results indicate that skin over muscle tolerates greater locally applied loads and deformations because the pressure is lower within the tissue than when similar loads and deformation are applied to skin over bone. Cutaneous perfusion, as indicated by TcPO2, seems to be linked more closely to the subcutaneous tissue pressure than to the surface load or deformations. These results provide some data for predicting mechanical and physiologic response to locally applied loads such as those that may be encountered in prosthetic wear.

Lower-extremity rotational problems in children. Normal values to guide management.

We studied 1,000 normal lower extremities of children and adults in order to establish normal values for the rotational profile. The intrauterine position of the fetus molds the femur by rotating it laterally and molds the tibia by rotating it medially. These molding effects usually resolve spontaneously during infancy, and then genetically determined individual differences are unmasked. Rotational problems should be clinically evaluated and the findings compared with the normal values provided by this study. Out-toeing in infants, medial tibial torsion in toddlers, and medial femoral torsion in young children are extremes of a normal developmental pattern. In the vast majority, these rotational variations fall within the broad range of normal and require no treatment.

Total shoulder arthroplasty.

A prospective study was done of fifty total shoulder replacements in forty-four patients who were followed for an average of 3.5 years (range, 2.0 to 7.5 years). The preoperative diagnosis was osteoarthritis in thirty-three shoulders, rheumatoid arthritis in eleven, and a previous fracture of the humeral head in six shoulders. Nine of the shoulders had a tear of the rotator cuff. The Neer-II system of total shoulder replacement with a non-metal-backed component was used in all fifty shoulders. At follow-up, forty-four shoulders (88 per cent) had no significant pain. Of the six painful shoulders, four had loosening of the glenoid component and one had malposition of both components. Three of the six shoulders had no significant pain after revision. The average range of active forward elevation in all of the shoulders improved from 71 to 100 degrees, and both external and internal rotation improved as well. Five specific activities of daily living were evaluated, and the patients' ability to perform them improved from 14 to 78 per cent. Thirty-five shoulders (68 per cent) were rated by the patients as much better; thirteen shoulders (26 per cent), as better; and three (6 per cent), as no better. An incomplete lucent line was noted around five (10 per cent) of the cemented humeral stems and around thirty-seven (74 per cent) of the glenoid prostheses. Four arthroplasties (8 per cent) required revision: three for loosening of the glenoid component and one for malposition of both components.(ABSTRACT TRUNCATED AT 250 WORDS)

Transcutaneous oxygen tension as a predictor of success after an amputation.

We measured local transcutaneous oxygen tension at the foot and proximal and distal to the knee in 162 patients who then had 206 amputations. When the values for oxygen tension at the foot and distal to the knee were compared with the success or failure of healing after an amputation of the foot or distal to the knee, respectively, a clearly increasing probability of failure was correlated with decreasing transcutaneous oxygen tension. However, even at a tension of zero the probability of failure was not 100 per cent. The results were similar for diabetic and non-diabetic patients. Preoperative values for transcutaneous oxygen tension were a much more consistent predictor of success or failure of healing after an amputation of the foot or distal to the knee than were measurements of systolic blood pressure at the ankle, but neither was predictive of the outcome after an above-the-knee amputation.

Segmental transcutaneous measurements of PO2 in patients requiring below-the-knee amputation for peripheral vascular insufficiency.

An accurate method is needed to quantitate the healing potentials of the possible sites of amputation in dysvascular limbs. We evaluated the segmental transcutaneous measurements of PO2 in thirty-seven patients who required below-the-knee amputation because of peripheral vascular insufficiency. The fifteen patients with below-the-knee transcutaneous PO2 values of forty millimeters of mercury or more had no delay in healing of the below-the-knee amputation. Seventeen of nineteen patients with values of more than zero but less than forty millimeters of mercury had healing at the below-the-knee level, in two after local revision. The three patients who had below-the-knee values of zero required re-amputation above the knee.

Tetrahydrobiopterin increases myocardial blood flow in healthy volunteers: a double-blind, placebo-controlled study.

OBJECTIVES: Tetrahydrobiopterin (BH4) is a regulatory cofactor for the activity of nitric oxide synthases. Vasodilating properties of BH4 have been reported in vitro and in vivo. The influence of BH4 on myocardial blood flow (MBF), however, is largely unknown. We therefore performed a double-blind, placebo-controlled study to investigate the effect of intravenous BH4 on MBF in healthy volunteers. METHODS AND RESULTS: Resting MBF was assessed in 15 subjects receiving either intravenous BH4 (10 mg/kg) or placebo using positron emission tomography (PET) and [13N]ammonia. From a mean baseline MBF of 0.91 +/- 0.09 ml/min/g, MBF increased to 1.18 +/- 0.10 ml/min/g after BH4 (n = 10; p = 0.0042). In contrast, in the group receiving placebo mean MBF remained unchanged (non-significant decrease from 0.97 +/- 0.19 to 0.84 +/- 0.11 ml/min/g; n = 5; p = 0.36). Systemic haemodynamics and ECGs remained unaffected in both groups. BH4 was very well tolerated. CONCLUSION: Systemically administered BH4 is safe and effectively increases resting MBF in healthy volunteers.

Support of peptide-dependent growth of Bacteroides forsythus by synthetic fragments of haemoglobin or fetuin.

The putative periodontal pathogen Bacteroides forsythus is a fastidious Gram-negative anaerobe with high proteolytic activity. For growth in a chemically defined medium containing insulin it required serum. Serum could be replaced by human haemoglobin or bovine asialofetuin, or by proteolytic fragments of these two proteins. Four such fragments consisting of from 8 to 18 amino acid residues were isolated and sequenced. Only aspartic acid, threonine, and valine were common to all peptides. An undecapeptide, Hba11, and a dodecapeptide, AsF12, were synthesized and found to be active at micromolar concentrations, but only when presented in combination with insulin. An analysis of amino acid requirements excluded a direct essential role of peptides as sources of amino acids in complete medium, except for valine. Should Bact. forsythus have an essential requirement for this amino acid, it could be satisfied by micromolar concentrations of peptide but not millimolar concentrations of the free amino acid in the absence of peptide. Bact. forsythus could salvage the essential amino acids lysine and isoleucine at 100-fold lower concentrations when presented in peptide-bound form compared to the free amino acids, and at 10-fold lower concentrations of peptide compared to Porphyromonas gingivalis W83, which in contrast to Bact. forsythus grew on free amino acids in the absence of insulin and peptides.