Reconstructive vascular surgery and the extent of tissue damage due to diabetic foot ulcers relates to risk of new ulceration in patients with PAD.

OBJECTIVE: There is limited information regarding new ulceration following the healing of ischaemic foot ulcers in diabetic patients. Our aim is to study new ulcerations in the same foot as the previous ulcer(s) in patients with diabetes and severe peripheral artery disease (PAD). METHOD: Patients with diabetes and severe PAD who healed from previous ulcer(s) (Wagner grade 1-5, at or below the ankle), were recruited for the prospective study from the time of healing of their ulcer. Patients were followed up regarding new ulceration, and their treatments and ulcer status noted either directly or on examination of medical records. RESULTS: We analysed the data on 602 patients with diabetes and severe PAD with healed foot ulcers, either primarily (n=443, 74%) or after minor amputation (n=159, 26%). Of these 51% (n=305) had revascularisation before healing from the previous ulcer, 34% (n=202) developed a new ulcer on the same foot within 15 months (range 0-106). Amputation was required by 22% (n=45) of patients, with a new ulcer on the same foot. The median survival time of all patients (n=602) was 54 months. By regression analysis, a low maximal Wagner grade for the previous ulcer and reconstructive vascular surgery was related to a decreased risk of developing new ulcers in the same foot. CONCLUSION: Patients with diabetes and ischaemic foot ulcers have a high-risk for developing new ulcers and amputation in the same foot after healing. The extent of tissue involvement in the previous ulcer and reconstructive vascular surgery affected the risk for development of new ulcers.

Early revascularization after admittance to a diabetic foot center affects the healing probability of ischemic foot ulcer in patients with diabetes.

OBJECTIVES: There is limited information about whether time from recognition of decreased perfusion to revascularization affects the probability of healing in a patient with a diabetic foot ulcer. The aim of the present study was to examine whether time to revascularization after referral to a multidisciplinary foot center was related to the outcome of foot ulcers in patients with diabetes and severe peripheral arterial disease (PAD). METHODS: Patients with diabetes, a foot ulcer, and a systolic toe pressure <45 mmHg or an ankle pressure <80 mmHg were prospectively included at the foot center, and considered for revascularization according to a preset protocol. All patients underwent invasive revascularization, either percutaneous transluminal angioplasty (PTA) or reconstructive vascular surgery. All patients had continuous follow-up until healing or death irrespective of the type of revascularization. RESULTS: A total of 478 patients were included (age 74 [range 66-80] years, 60% males), of whom 315 patients (66%) had PTA, and 163 (34%) had reconstructive surgery. Of the 478 patients, 217 (45%) healed primarily, 88 (19%) healed after a minor amputation, 76 (16%) healed after a major amputation and 92 patients (19%) died unhealed. The median time from inclusion in the study to revascularization was 8 weeks (3-18 weeks). Time to vascular intervention within 8 weeks (p < .001), maximum Wagner grade reached <3 (p < .001), absence of peripheral edema (p = .033), and presence of intermittent claudication (p = .001) were related to a higher probability of healing. CONCLUSIONS: Time to revascularization and extent of tissue damage were related to the probability of healing of ischemic foot ulcer in patients with diabetes over time. In the presence of a decreased perfusion in a patient with diabetes and a foot ulcer not only revascularization per se but also timing of revascularization is important for the possibility of healing without a major amputation.

Toll-like receptor 9 ligands enhance mesenchymal stem cell invasion and expression of matrix metalloprotease-13.

Human mesenchymal stem cells (hMSCs) are multipotent cells that are found in the bone marrow. Inflammation and tissue damage mobilize MSCs and induce their migration towards the damaged site through mechanisms that are not well defined. Toll-like receptor-9 (TLR9) is a cellular receptor for microbial and vertebrate DNA. Stimulation of TLR9 induces inflammatory and invasive responses in TLR9-expressing cells. We studied here the expression of TLR9 in human MSCs and the effects of synthetic TLR9-agonists on their invasion. Constitutive expression of TLR9 was detected in human MSCs but the expression was suppressed when MSCs were induced to differentiate into osteoblasts. Using standard invasion assays and a novel organotypic culture model based on human myoma tissue, we discovered that stimulation with the TLR9 agonistic, CpG oligonucleotides increased the invasion capacity of undifferentiated MSCs. Simultaneously, an increase in MMP-13 synthesis and activity was detected in the CpG-activated MSCs. Addition of anti-MMP-13 antibody significantly diminished the CpG-induced hMSC invasion. We conclude that treatment with TLR9-ligands increases MSC invasiveness, and this process is at least partially MMP-13-mediated.

MMP8 increases tongue carcinoma cell-cell adhesion and diminishes migration via cleavage of anti-adhesive FXYD5.

Matrix metalloproteinases (MMPs) modify bioactive factors via selective processing or degradation resulting in tumour-promoting or tumour-suppressive effects, such as those by MMP8 in various cancers. We mapped the substrates of MMP8 to elucidate its previously shown tumour-protective role in oral tongue squamous cell carcinoma (OTSCC). MMP8 overexpressing (+) HSC-3 cells, previously demonstrated to have reduced migration and invasion, showed enhanced cell-cell adhesion. By analysing the secretomes of MMP8 + and control cells with terminal amine isotopic labelling of substrates (TAILS) coupled with liquid chromatography and tandem mass spectrometry (LC-MS/MS), we identified 36 potential substrates of MMP8, including FXYD domain-containing ion transport regulator 5 (FXYD5). An anti-adhesive glycoprotein FXYD5 has been previously shown to predict poor survival in OTSCC. Cleavage of FXYD5 by MMP8 was confirmed using recombinant proteins. Furthermore, we detected a loss of FXYD5 levels on cell membrane of MMP8 + cells, which was rescued by inhibition of the proteolytic activity of MMP8. Silencing (si) FXYD5 increased the cell-cell adhesion of control but not that of MMP8 + cells. siFXYD5 diminished the viability and motility of HSC-3 cells independent of MMP8 and similar effects were seen in another tongue cancer cell line, SCC-25. FXYD5 is a novel substrate of MMP8 and reducing FXYD5 levels either with siRNA or cleavage by MMP8 increases cell adhesion leading to reduced motility. FXYD5 being a known prognostic factor in OTSCC, our findings strengthen its potential as a therapeutic target.

Complexity of factors related to outcome of neuropathic and neuroischaemic/ischaemic diabetic foot ulcers: a cohort study.

AIMS/HYPOTHESIS: We sought to identify factors related to short-term outcome of foot ulcers in patients with diabetes treated in a multidisciplinary system until healing was achieved. METHODS: Consecutively presenting patients with diabetes and worst foot ulcer (Wagner grade 1-5, below ankle) (n = 2,511) were prospectively followed and treated according to a standardised protocol until healing was achieved or until death. The number of patients lost to dropout was 31. The characteristics of the remaining 2,480 patients were: 1,465 men, age 68 +/- 15 years (range 18-96), type 1 diabetes 18%, type 2 diabetes 82% and insulin-treated 62%. RESULTS: The healing rate without major amputation in surviving patients was 90.6% (n = 1,867). Sixty-five per cent (n = 1,617) were healed primarily, 9% (n = 250) after minor amputation and 8% after major amputation; 17% (n = 420) died unhealed. Out of 2,060 surviving patients, 1,007 were neuroischaemic (48.8%). In a multiple regression analysis, primary healing was related to co-morbidity, duration of diabetes, extent of peripheral vascular disease and type of ulcer. In neuropathic ulcers, deep foot infection, site of ulcer and co-morbidity were related to amputation. Amputation in neuroischaemic ulcers was related to co-morbidity, peripheral vascular disease and type of ulcer. Age, sex, duration of diabetes, neuropathy, deformity and duration of ulcer or site of ulcer did not have an evident influence on probability of amputation. CONCLUSIONS/INTERPRETATION: Patients with diabetic foot ulcer suffer from multi-organ disease. Factors related to outcome are correspondingly complex.

Parental expectations, experiences and reactions, sense of coherence and grade of anxiety related to routine ultrasound examination with normal findings during pregnancy.

OBJECTIVE: To investigate parents' expectations, experiences and reactions, sense of coherence and anxiety before and after a second-trimester routine ultrasound examination, with normal findings. METHODS: Before and after ultrasound questionnaires including the scales parents' expectations, experiences and reactions to routine ultrasound examination (PEER-U state of mind index), sense of coherence (SOC) and state and trait anxiety inventory (STAI), were sent to a 1-year cohort of women and their partners. Replies received were 2183. RESULTS: Both parents had significantly less worried state of mind (PEER-U) after the examination than before. Women had a lower grade of state anxiety after than before, but for men there was no significant change. Before the ultrasound, women had a higher degree of worried state of mind, as well as a higher grade of state and trait anxiety and a lower sense of coherence, than men. The women showed a greater reduction in worried state of mind than the men after the ultrasound examination. There were no significant differences in sense of coherence before and after ultrasound. CONCLUSIONS: Women and men are affected in their psychological well-being in relation to a routine ultrasound examination, but their sense of coherence remains stable.

Sociodemographic risk factors of metabolic syndrome in middle-aged women: results from a population-based study of Swedish women, The Women's Health in the Lund Area (WHILA) Study.

BACKGROUND: Metabolic syndrome (MS) is a common health problem in menopausal women. According to The Adult Treatment Panel (ATP) III, MS includes the combination of three or more of the following risk factors: abdominal obesity, glucose intolerance, high blood pressure, high serum triglycerides and low levels of high density lipoprotein cholesterol. OBJECTIVES: To assess the prevalence of the MS in middle-aged women, and the relationships of sociodemographic factors to the MS. METHODS: This analysis covers 10,766 women born between December 2, 1935 and December 1, 1945, living in the Lund area of Sweden by December 1, 1995. RESULTS: We found that 11.6% of women with a mean (+/-standard deviation) age of 56.9 +/- 3.06 years had MS. Women with MS were older and had higher scores for body weight, body mass index, waist/hip ratio, pulse rate, pulse pressure, serum triglycerides and total serum cholesterol (p < 0.001 for all) compared to the control group. More MS women were smokers, less often consumers of alcohol, and less qualified. In addition, they had low-intensity physical activity at leisure time (p < 0.001) and high-intensity physical activity at work (p = 0.009). Premenopausal women and those treated with hormones had less MS (p < 0.001). Education, physical activity at leisure time, moderate intensity of physical activity at work, alcohol intake and smoking had strong association with MS but work status, household status and dietary habits had no significant association with MS. CONCLUSIONS: Sociodemographic features may contribute to MS. Hence, prevention of MS should encompass sociodemographic features.

Obstructive airways diseases, smoking and use of inhaled corticosteroids in southern Sweden in 1992 and 2000.

OBJECTIVE: To examine the prevalence of obstructive pulmonary diseases, respiratory symptoms, smoking habits and pulmonary medication in an adult population, and to compare the results with a study performed in the same geographical area in 1992. DESIGN: In 2000, a postal questionnaire was sent to a randomly selected population of 5179 subjects aged 20-59 years living in southern Sweden. RESULTS: The participation rate was 71.3%. Self-reported asthma was reported by 8.5% of all respondents (vs. 5.5% in 1992, P < 0.001) and 14.5% of females aged 20-29 years. Self-reported chronic bronchitis and/or emphysema and/or chronic obstructive pulmonary disease (CBE/COPD) was reported by 3.6% (vs. 4.6% in 1992, non-significant) with the highest prevalence (5.7%) in the 50-59 year cohort. Smoking decreased from 33.3% in 1992 to 28.4% in 2000 (P < 0.05). About 46% of asthmatics reported nocturnal respiratory symptoms, and 69% reported having had asthma symptoms in the last 12 months. Use of inhaled steroids increased in subjects with asthma and CBE/COPD from 19.4% to 36.5% (P < 0.05) and from 8.6% to 30.0% (P < 0.05), respectively. CONCLUSIONS: Self-reported asthma increased significantly between 1992 and 2000, but the prevalence of CBE/COPD was unchanged. The high proportion of reported symptoms in asthmatics despite an increased use of steroids suggests that further efforts are needed to improve asthma treatment.

Does the Introduction of Laparoscopic Distal Pancreatectomy Jeopardize Patient Safety and Well-Being?

BACKGROUND/PURPOSE: Despite retrospective data indicating short-term superiority for laparoscopic distal pancreatectomy compared to open distal pancreatectomy, the implementation of the procedure has been slow. The aim of this study was to investigate whether patients operated with laparoscopic distal pancreatectomy during the early phase of introduction are at higher risk for complications than patients operated with open distal pancreatectomy. METHODS: A retrospective single-center analysis of patients operated with laparoscopic distal pancreatectomy (n = 37) from the introduction of the procedure and comparison regarding demographic data, preoperative data, operative factors, and postoperative outcomes to patients operated with open distal pancreatectomy was done. RESULTS: Operation duration shortened (195 vs 143 min, p = 0.04) and severe complications reduced (37% vs 6%, p = 0.02) significantly in the laparoscopic distal pancreatectomy group between the first half of the study and the second half. Blood loss was significantly (p < 0.001) lower in the laparoscopic distal pancreatectomy group (75 mL) than in the open distal pancreatectomy group (550 mL), while complication rate and hospital stay as well as the percentage of radical resections were the same. CONCLUSION: Laparoscopic distal pancreatectomy can be introduced without jeopardizing patient safety and well-being during the early learning curve. The procedures should be compared in a prospective randomized manner.

Serotonin concentrations in normal aging human brains: relation to serotonin receptors.

Concentrations of serotonin (5-HT) and its deaminated metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured in 7 regions of normal human brains and, in some of the regions, were compared to the number of serotonin receptors (S1 and S2). Neither 5-HT nor 5-HIAA concentrations correlated significantly with increasing age (from 17-100 years) in any of the regions investigated. Positive correlations between 5-HT and 5-HIAA were found in all regions studied, significantly (p less than 0.05) so in 5 of the areas. When comparing 5-HT transmitter and metabolite concentrations to the number of S1 and S2 receptors, no significant correlations were found either within any brain area of between different brain regions. These data confirm that 5-HT transmitter concentrations are not altered by increasing age, support the ideas that S1 and S2 receptors are not presynaptic and also that 5-HT transmitter concentrations and receptor densities are separately controlled.

Divergent changes in D-1 and D-2 dopamine binding sites in human brain during aging.

The density of D-1 and D-2 dopamine receptors in human caudate nucleus and putamen, obtained postmortem, were studied throughout the adult lifespan using [3H]fluphenazine as the dopamine receptor ligand. The D-1 subtype increased progressively with age in both regions, while the D-2 subtype declined in caudate nucleus. The ratio of D-1/D-2 Bmax in both regions increased from approximately 1 at age 20 to 2 by age 75. The dopamine content in putamen declined with age and was inversely correlated with D-1 receptor density. We suggest that D-1 receptor density is up-regulated by loss of dopamine during aging. The D-2 receptor density in caudate nucleus was positively correlated with choline acetyltransferase activity, suggesting that loss of intrastriatal neurons with age may contribute to the decrease in D-2 sites. These divergent changes in dopamine receptor subtypes with age result in an altered complement of dopamine receptors in older humans and may provide a basis for selective pharmacotherapy in disorders of the basal ganglia.

The SHBG-like region of protein S is crucial for factor V-dependent APC-cofactor function.

Activated protein C (APC) regulates blood coagulation by degrading factor Va (FVa) and factor VIIIa (FVIIIa). Protein S is a cofactor to APC in the FVa degradation, whereas FVIIIa degradation is potentiated by the synergistic APC-cofactor activity of protein S and factor V (FV). To elucidate the importance of the sex-hormone-binding globulin (SHBG)-like region in protein S for expression of anticoagulant activity, a recombinant protein S/Gas6 chimera was constructed. It comprised the amino-terminal half of protein S and the SHBG-like region of Gas6, a structurally similar protein having no known anticoagulant properties. The protein S/Gas6 chimera expressed 40-50%, APC-cofactor activity in plasma as compared to wild-type protein S. In the degradation of FVa by APC, the protein S/Gas6 chimera was only slightly less efficient than wild-type protein S. In contrast, the protein S/Gas6 chimera expressed no FV-dependent APC-cofactor activity in a FVIIIa-degradation system. This demonstrates the SHBG-like region to be important for expression of APC-cofactor activity of protein S and suggests that the SHBG-like region of protein S interacts with FV during the APC-mediated inactivation of FVIIIa.

Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines.

The atherosclerotic lesion contains large numbers of macrophages and T lymphocytes. This suggests that a cellular immune response may take place in the lesion, and oxidized lipoproteins, heat shock proteins, and micro-organisms have been implied as candidate antigens. However, the effector mechanisms elicited by this response have been largely unclear. We have therefore analyzed endarterectomy specimens by immunohistochemistry and reverse transcription-PCR to detect immune cytokines produced by immunocompetent cells of the advanced human plaque. The pro-inflammatory T cell cytokines, interleukin-2 and interferon-7, were found in a large proportion of plaques (IL-2 in 50% and interferon-gamma in 30% of plaques by immunohistochemistry and mRNA for both cytokines in 70% of plaques by PCR). In contrast, interleukin-4 and interleukin-5 were rarely observed (both cytokines in 10% of plaques by immunohistochemistry, mRNA for interleukin-4 in 10% and for interleukin-5 in 40% by PCR). This demonstrates the presence of a predominantly pro-inflammatory, Th1-type T cell response in atherosclerosis. This conclusion was further supported by the expression of the pro-inflammatory cytokine, interleukin-1 by plaque macrophages and endothelial cells. In addition, the chemokine interleukin-8 and the macrophage differentiation-stimulating cytokine, granulocyte-monocyte colony stimulating factor, were observed in plaque tissues, suggesting that the micro-environment promotes monocyte recruitment and macrophage differentiation. Occasional eosinophils and B cells were, however observed, which is compatible with a microheterogeneity within the lesion. Finally, the anti-inflammatory and fibrogenic cytokines, transforming growth factor-beta1-3 and its carrier protein, latent TGF-beta binding protein, were found in large amounts in all plaques. Together, these results show that a pro-inflammatory, Thl type cellular immune response takes place in the atherosclerotic plaque. The balance between pro-inflammatory and anti-inflammatory cytokines may be decisive for the progression of the lesion.

Low birth weight is associated with elevated systolic blood pressure in adolescence: a prospective study of a birth cohort of 149378 Swedish boys.

OBJECTIVES: To determine the association between birth weight and systolic blood pressure (SBP) in male adolescents at the age of 18 years. DESIGN: A prospective study by means of a register linkage between the Swedish Medical Birth Register and the national register for conscript testing before military service. METHODS: From the birth registry we collected data on birth weight, gestational age, maternal age and parity for 149378 individuals. At conscript testing, subjects were given a physical examination, and weight, height, and mean blood pressure were recorded after 5-10 min rest. RESULTS: Mean+/-SD birth weight was 3543+/-551 g after a mean of 39.7+/-2.0 gestational weeks. Mean+/-SD blood pressure at the conscript testing was 128.8+/-10.9/65.2+/-10.6 mmHg. SBP, but not diastolic blood pressure, differed significantly (test for trend, P< 0.001) between birth weight strata (deciles), with a higher SBP in strata with lower birth weight. A difference in birth weight of 1000 g decreased SBP by 0.8 mmHg. This was most pronounced in subjects with a rapid growth development (n = 1057), coming from the lowest decile of birth weight and reaching to the highest decile of body mass index, in a very consistent manner. The odds ratio for being in the top decile of SBP was 1.55 (95% confidence interval 1.32-1.81) for this growth 'catch-up' group compared with the rest of the cohort. CONCLUSIONS: Birth weight was inversely associated with SBP in a large cohort of young men in their late teens. This supports the notion of a programming effect of fetal growth retardation in utero on haemodynamic regulation in early adult life.

Similar pleural fluid findings in pleuropulmonary tularemia and tuberculous pleurisy.

Biochemical and cellular characteristics of pleural fluid from two patients with pleuropulmonary tularemia and 39 patients with tuberculous pleurisy were compared. High pleural fluid concentrations of adenosine deaminase, lysozyme, and beta 2-microglobulin occurred in both diseases. As is the case with tuberculous pleural effusions, pleural fluid in tularemia showed an abundance of lymphocytes, predominantly CD4-positive T lymphocytes. The similar pleural fluid findings suggest analogous local pathogenetic mechanisms in tularemia and tuberculosis. In the diagnostic evaluation of a lymphocyte-rich exudative pleural effusion with a high adenosine deaminase concentration, a possible cause to consider is tularemia.

Quartz-induced production of reactive oxygen metabolites by activated human monocyte-derived macrophages.

Quartz but not titanium dioxide (TiO2) induced the production of reactive oxygen metabolites (ROM) by human monocyte-derived macrophages, as measured by lucigenin dependent chemiluminescence. Activation of the macrophages with BCG, bacterial lipopolysaccharide and macrophage-activating factor (MAF) caused a prominent increase of quartz-induced ROM production, MAF having the strongest effect. The activation did not affect the TiO2 responses to the same extent. Assuming that ROM have a role in the pathogenesis of silica-induced disease in man, we suggest that enhancement of quartz-induced production of ROM by activated pulmonary macrophages may at least partly explain the experimental and epidemiological data indicating that activation of the immune system during infection promotes the development of silicosis.

A synergistic interaction between Bacillus Calmette-Guérin (BCG) and NADPH oxidase stimulants on the production of reactive oxygen metabolites by human mononuclear phagocytes.

Bacillus Calmette-Guérin (BCG) was added simultaneously with known NADPH oxidase stimulants to suspensions of human mononuclear leukocytes, and the subsequent production of reactive oxygen metabolites (ROMs) was studied by luminol-dependent chemiluminescence. BCG significantly amplified the ROM responses induced by zymosan, phorbol myristate acetate (PMA), and quartz, but not by concanavalin A and asbestos fibers. The stimulatory effect occurred rapidly when BCG was added to cells already phagocytosing zymosan, and vanished rapidly when extracellular BCG was removed from adherent monocyte cultures by washing prior to the addition of zymosan. The stimulatory effect of BCG could not be reproduced with recombinant interferon-gamma, tuberculin PPD, muramyl dipeptide, nor with the apathogenic Mycobacterium tuberculosis strain RV37. BCG and zymosan or PMA that had been incubated together prior to addition to the mononuclear cell suspensions caused ROM production with faster kinetics than if the reagents were added separately without preincubation. In conclusion, the synergy between BCG and some of the NADPH oxidase stimulants seems to be due to an interaction between BCG and the NADPH oxidase stimulants rather than to an interaction between BCG and the ROM-producing cells. Such interactions between mycobacteria and NADPH oxidase stimulants may be of importance as a factor affecting the individual susceptibility to tissue damage in tuberculosis, for example in silicotuberculosis.

Increased mineral dust-induced production of reactive oxygen species by blood monocytes from patients with malignant diseases.

Mononuclear leukocytes were isolated from the peripheral blood of 15 patients with malignant pulmonary diseases, 17 patients with pulmonary infections, 18 patients with chest film abnormalities of non-malignant, non-infectious etiology, and 15 healthy persons. The cells were exposed to zymosan yeast, BCG vaccine, quartz, or chrysotile asbestos, and the subsequent production of reactive oxygen species (ROS) was measured by luminol-dependent chemiluminescence. All the stimulants caused significantly higher ROS production in the patient groups than in the healthy control group, and the asbestos-induced ROS production was significantly more pronounced in the cancer group than in the two non-cancer patient groups combined. After one-year follow-up, 5 of the 15 cancer patients were alive, and these patients had significantly lower mineral dust-induced ROS responses at the time of diagnosis than were found in the patients who died. This result was verified in a subsequent study comprising 19 patients with malignant pulmonary disorders (6 alive after one year). In conclusion, monocytes from patients with malignant diseases seem to be primed for an increased ROS production, and high ROS responses seem to correlate with a poor one-year survival of the patients.

Increased susceptibility to stress at a psychological assessment of stress tolerance is associated with impaired fetal growth.

BACKGROUND: This study aims to investigate the relationship between birthweight and psychological function, as evaluated by the results of a psychological conscript interview and assessment in young males, including an evaluation of stress susceptibility. METHODS: We performed a retrospective cohort study based on linked birth registry data and data from an assessment of psychological function during evaluation for military service. In all, 90 651 young males born 1973-1975, for whom birth record data were obtained from the Swedish Medical Birth Register, were investigated in addition to psychological stress susceptibility during their conscript evaluation in 1991-1994. The assessment of psychological functioning score, including the assessment of stress susceptibility, was used as the dependent variable in a multiple regression analysis in combination with the following independent variables: birthweight, adult weight, head circumference at birth, month of birth, gestational age, maternal parity, and maternal age. RESULTS: The mean value was 5.1 (SD 1.9) on the psychological assessment scale (range 1-9) of psychological level of functioning including evaluation of stress susceptibility, and 5.3 (1.6) on the general psychological performance (leadership) profile. A positive association was seen between birthweight and better assessment results up to a level of about 4000 g birthweight, but above that an inverse association was seen. Positive correlations (P < 0.001) were seen between psychological assessment score results and birthweight (r = 0.07), gestational age (0.03), head circumference (0.05), and maternal age (0.11), but inverse correlations with maternal parity (-0.11) and birth month of the offspring (-0.04). In multiple regression analyses, the strongest independent correlations were seen between increasing assessment scores and maternal age and birthweight (positive), as well as with maternal parity and offspring adult weight (negative). CONCLUSION: Young males at conscript testing show a better general psychological functioning score derived from psychological assessment, including evaluation of stress susceptibility, with increasing birthweight up to 4200 g. Above that birthweight an inverse association is noticed. Impaired fetal growth is predictive of suboptimal psychological functioning and increased stress susceptibility in males during early adult life.

Transmitter deficits in Alzheimer's disease.

The pattern of neurotransmitter pathway losses in Alzheimer's disease are reviewed. Deficits of the cholinergic pathway from the nucleus basalis, the noradrenergic pathway from the locus coeruleus and the serotoninergic pathway from the raphe nuclei are established. Cortical somatostatin interneurons are affected and dopaminergic neurons may be affected although these may be late or secondary phenomena in the disease process. Other neuronal systems, particularly in the hippocampus and temporal cortex, are also damaged. However, the disease is not one of generalised neuronal atrophy since some neurons are selectively spared. The established pathway-specific losses are discussed in relation to the clinical symptomatology and the pathology of the disorder. The biochemical and histological findings are compared with similar measurements made on tissues from other dementing disorders in an attempt to trace features common to dementias. Finally, as an addendum, a hypothesis is briefly outlined which attempts to explain the common features of the affected neurons and the pathogenesis of the disorder.