Offspring death and subsequent psychiatric morbidity in bereaved parents: addressing mechanisms in a total population cohort.

BACKGROUND: It is unclear if psychiatric morbidity among parents bereaved of a child is related to major loss in general or if the cause of death matters. Whether such a link is consistent with a causal explanation also remains uncertain. METHOD: We identified 3,114,564 parents through linkage of Swedish nationwide registers. Risk of psychiatric hospitalization was assessed with log-linear Poisson regression and family-based analyses were used to explore familial confounding. RESULTS: A total of 3284 suicides and 14,095 any-cause deaths were identified in offspring between 12 and 25 years of age. Parents exposed to offspring suicide had considerably higher risk of subsequent psychiatric hospitalization than unexposed parents [relative risk (RR) 1.90, 95% confidence interval (CI) 1.72-2.09], higher than parents exposed to offspring non-suicide death relative to controls (RR 1.18, 95% CI 1.11-1.26). We found no risk increase among stepfathers differentially exposed to biologically unrelated stepchildren's death or suicide, and the relative risk was notably lower among full siblings differentially exposed to offspring death or suicide. CONCLUSIONS: Parental psychiatric hospitalization following offspring death was primarily found in offspring suicide. Familial (e.g. shared genetic) effects seemed important, judging from both lack of psychiatric hospitalization in bereaved stepfathers and attenuated risk when bereaved parents were contrasted to their non-bereaved siblings. We conclude that offspring suicide does not 'cause' psychiatric hospitalization in bereaved parents.

Parental schizophrenia and increased offspring suicide risk: exploring the causal hypothesis using cousin comparisons.

BACKGROUND: Little is known about suicide risk among offspring of parents hospitalized for schizophrenia and the mechanisms behind this association. METHOD: We applied a nested case-control design based on linkage of Swedish population-based registers. Among 12- to 30-year-old offspring, we identified 68 318 offspring with suicidal behavior (attempted and completed suicide) and their parents. Five healthy control-parent pairs were matched to each suicidal case-parent pair and conditional logistic regression used to obtain odds ratios (ORs). Further, to disentangle familial confounding from causal environmental mechanisms, we compared the population-based suicide risk with the risk found within full-cousins and half-cousins differentially exposed to parental schizophrenia. RESULTS: Offspring of parents with schizophrenia had significantly increased suicide risk after accounting for socio-economic status, parental suicidal behavior and offspring mental illness [OR 1.68, 95% confidence interval (CI) 1.53-1.85]. Suicide risks in offspring of schizophrenic mothers and fathers were similar in magnitude; so were risks across different developmental periods. Importantly, offspring suicide risk remained essentially unchanged across genetically different relationships; offspring of siblings discordant for schizophrenia had equivalent risk increases within full-cousins (OR 1.96, 95% CI 1.66-2.31) and half-cousins (OR 1.69, 95% CI 1.17-2.44). CONCLUSIONS: Parental schizophrenia was associated with increased risk of offspring suicidal behavior, independent of gender of the schizophrenic parent, and persisting into adulthood. The suicide risk in offspring remained at a similar level when comparing genetically different relationships, which suggests that at least part of the association is due to environmental mechanisms. These findings should inspire increased attention to suicidal ideation and prevention efforts in offspring of parents with schizophrenia.

Genetic and environmental influences on adult attention deficit hyperactivity disorder symptoms: a large Swedish population-based study of twins.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) frequently persists into adulthood. Family and twin studies delineate a disorder with strong genetic influences among children and adolescents based on parent- and teacher-reported data but little is known about the genetic and environmental contribution to DSM-IV ADHD symptoms in adulthood. We therefore aimed to investigate the impact of genetic and environmental influences on the inattentive and hyperactive-impulsive symptoms of ADHD in adults. METHOD: Twin methods were applied to self-reported assessments of ADHD symptoms from a large population-based Swedish twin study that included data from 15 198 Swedish male and female twins aged 20 to 46 years. RESULTS: The broad heritability [i.e., A + D, where A is an additive genetic factor and D (dominance) a non-additive genetic factor] was 37% (A = 11%, D = 26%) for inattention and 38% (A = 18%, D = 20%) for hyperactivity-impulsivity. The results also indicate that 52% of the phenotypic correlation between inattention and hyperactivity-impulsivity (r = 0.43) was explained by genetic influences whereas the remaining part of the covariance was explained by non-shared environmental influences. These results were replicated across age strata. CONCLUSIONS: Our findings of moderate broad heritability estimates are consistent with previous literature on self-rated ADHD symptoms in older children, adolescents and adults and retrospective reports of self-rated childhood ADHD by adults but differ from studies of younger children with informant ratings. Future research needs to clarify whether our data indicate a true decrease in the heritability of ADHD in adults compared to children, or whether this relates to the use of self-ratings in contrast to informant data.

Cognitive impairment in patients with stress-related exhaustion.

Patients who seek medical care for stress-related mental health problems frequently report cognitive impairments as the most pronounced symptom. The purpose of the present study was to compare cognitive function in patients with stress-related exhaustion with that in healthy controls, using a comprehensive battery of cognitive tests. We also explored whether neuropsychological findings were related to severity of illness measured using the Shirom-Melamed burnout questionnaire and hospital anxiety and depression scale. Thirty-three patients (15 males) and 37 healthy controls (11 males), mean age 46 years [standard deviation (SD) 3.9] and 47 years (SD 4.3), respectively, were included in the final analysis. Five cognitive domains were assessed: (1) speed, attention and working memory, (2) learning and episodic memory, (3) executive functions, (4) visuospatial functions and (5) language. The most pronounced difference between patients and controls was seen on executive function, when tested with a multidimensional test, including aspects of speed, control and working memory. The patients also performed poorer on Digit span, measuring attention span and working memory as well as on learning and episodic memory, when measured as delayed recall and the difference between immediate and delayed recall. Delayed recall was the only test that was significantly related to severity of burnout symptoms among the patients. This could reflect poor cognitive sustainability in the patients with the highest burnout scores, as this particular test was the last one performed during the test session. This study clearly shows that cognitive impairment should be considered when evaluating and treating patients who seek medical care for stress-related exhaustion.

Early changes in rectal nitric oxide and mucosal inflammatory mediators in Crohn's colitis in response to infliximab treatment.

BACKGROUND: Treatment with tumor necrosis factor-alpha monoclonal antibody (infliximab) reduces clinical activity and intestinal inflammation in Crohn's disease. AIM: To study the time-course of the effects of infliximab with reference to mucosal cytokine and inducible nitric oxide synthase expression. METHODS: Thirty-two patients with Crohn's disease were treated with single dose infliximab (5 mg/kg). Disease activity was assessed days 1, 3, 7 and 28 using Harvey-Bradshaw index. Rectal nitric oxide levels were determined and rectal biopsies collected before treatment, 1 h after infusion and on days 3, 7 and 28. Immunohistochemical staining against inducible nitric oxide synthase, tumor necrosis factor-alpha, interleukin-1beta and interferon-gamma were performed. RESULTS: Clinical response was seen in 14 patients with down-regulation of global immunohistochemistry expression, reaching nadir day 3. Rectal nitric oxide was increased at baseline (3578 +/- 1199 parts per billion, ppb) compared with controls (89 +/- 13 ppb) (P < 0.001). In patients with clinical response, rectal nitric oxide decreased from 3926 +/- 1687 ppb to 1050 +/- 428 ppb day 28 (P < 0.05). CONCLUSIONS: Down-regulation of mucosal inflammatory mediators occurs after infliximab. Rectal nitric oxide levels parallel down-regulation of inducible nitric oxide synthase, tumor necrosis factor-alpha, interleukin-1beta and interferon-gamma and may serve as a quantitative biomarker of intestinal inflammation.

Nitrergic inhibition of migrating myoelectric complex in the rat is mediated by vasoactive intestinal peptide.

The role of vasoactive intestinal peptide (VIP) for the action of nitric oxide (NO) as a nonadrenergic noncholinergic inhibitory mediator was investigated regarding effects on migrating myoelectric complex (MMC) in rat. Animals were supplied with implanted bipolar electrodes at 5, 15 and 25 cm distal to pylorus for electromyography of small intestine. First, basal recordings with saline were followed by intravenous infusions of glyceryl trinitrate or VIP at different infusion rates to achieve dose-response relationships. Second, effects of different doses of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine (L-NNA) were studied. Third, the action of L-NNA (1 mg kg-1) on the effect of VIP (500 pmol kg-1 min-1), and of the VIP receptor antagonist (4-Cl-D-Phe6, Leu17), VIP (45 nmol 20 min-1), on the action of glyceryl trinitrate (44 nmol kg-1 min-1) was investigated. Glyceryl trinitrate prolonged the MMC cycle length from 16.3 +/- 1.3 to 44.9 +/- 8.0 min (P < 0.001), while VIP completely disrupted the MMC for the whole infusion period (P < 0.05). Higher doses of either compound induced quiescence. L-NNA shortened MMC cycle length from 14.7 +/- 1.2 to 8.6 +/- 1.4 min (P < 0.05), increased its propagation velocity from 2.0 +/- 0.4 to 18.3 +/- 8.4 cm min-1 (P < 0.01) and increased calculated length from 6.3 +/- 1.0 to 55.4 +/- 18.4 cm (P < 0.01). Pretreatment with (4-Cl-D-Phe6, Leu17) VIP blocked the inhibitory action of glyceryl trinitrate and preserved MMC pattern (P < 0.05). In contrast, L-NNA had no effect on the inhibition of MMC caused by VIP. Our results indicate that inhibition of MMC is related to production of NO, which may mediate its actions through VIP.

Colorectal carcinoma in ulcerative colitis is decreasing in Scandinavian countries.

A total of 31 cases with Ulcerative Colitis (UC) and colorectal carcinoma were retrieved from the files of the Karolinska Hospital, Stockholm between 1951 and 1998. Sections from 16 colectomy specimens (operable cases) and 15 biopsies obtained at laparotomy (inoperable cases), were available for the study. Of the 31 patients reported here, 22 (71%) were 49 years of age or younger at the time of surgery for carcinoma. In comparison only 47 (5.5 %) of the 855 colorectal carcinomas without UC reported in the Stockholm area in 1990 were 49years of age oryounger. When this hospital was a referral Center (1951 through 1969) 18 cases of carcinoma in UC were operated between 1951 and 1960 (1.8 patients/year), but only 4 between 1961 and 1969 (0.44 patients/year). During the surveillance period of 29 years (1970 to March 1998) only 9 patients (0.31 cases/year) were found to have carcinoma complicating UC. Notably, 8 of the 9 patients were operated on between 1970 and December 1989 (0.42 patients/year), but only one case between January 1990 and March 1998 (0.11 patients/year). The data presented indicate that the frequency of carcinoma cases in pancolitics has decreased at this hospital, not only during the referral period, from 1.8 patients/year during the 50's to 0.40 patients/year during the 60's, but also during the surveillance period (from 0.44 patients/year/during the 70's and 80's to 0.11 patients/year between 1990 and March 1998). This, despite the incidence of UC in the Stockholm County remained stable for the past 40 years (4.2 to 5 patients/10(5) inhabitants) and that the population in the Stockholm County has steady increased since 1950. A review of the present literature indicated that the ris for colorectal carcinoma in pancolitics is presently decreasing, not only in Sweden but also in other Scandinavian countries.

Successful long-term pancreatic islet cell xenotransplantation and functional tolerance in NOD mice.

These findings raise a high degree of optimism concerning the potential application of this modality in higher animals. Studies are currently in process in our laboratory to apply this immunosuppressive regimen to higher animals using xenogeneic pig islets in a preclinical model that would provide the basis for future clinical trials.

Deoxyspergualin is a unique immunosuppressive agent with selective utility in inducing tolerance to pancreas islet xenografts.

Recent studies of DSG have demonstrated that this agent has a unique ability among immunosuppressive drugs to induce long-term survival and functional tolerance of discordant islet xenografts from pig to the Lewis rat. In addition, DSG was found to be nontoxic to islet cells in culture and without any inhibitory effect upon insulin secretion in contrast to azathioprine, FK 506, and CyA. The long-term functional tolerance seen with these islets appears to involve a stable block of antidonor humoral immunity, although more testing is necessary to characterize the precise state producing functional tolerance in this model. Other studies presented at this meeting demonstrate the ability of DSG and RATG immunosuppression to produce long-term discordant islet survival in the NOD mouse, which suffers from a virulent autoimmune condition that destroys transplanted islets in most NOD models shortly after transplantation, even when the islets are microencapsulated. The functional tolerance is especially difficult to achieve with a discordant xenograft and thus the ability of RATG and DSG to achieve this impressive. Long-term studies using DSG and total lymphoid irradiation suggest that RATG is not essential to long-term survival but clearly it is quite synergistic with DSG and also has the advantage of being nontoxic. In fact, all animals receiving the DSG/RATG therapy were essentially free of toxicity and no deaths were observed that could be attributed to the drug therapy. This short-term course of administration of the drugs helped achieve this lack of toxicity. The high levels of synergism of ATG in this model could be related to the numerous monoclonal reactivities seen in polyclonal ATG with demonstrated titers of 1 to 4000 or greater for a number of specificities associated with B cells and macrophages, which could well be contributing to the block of humoral antibody previously demonstrated in DSG/RATG treated animals. The DSG, however, is especially effective in synergizing an antihumoral antibody response and can be shown to result in a striking decrease in early humoral antibody production following transplantation. Overall, these studies demonstrate a high potential of this immunosuppressive therapy to promote long-term discordant islet xenograft survival and functional tolerance without chronic rejection or the islet toxicity common to the currently used immunosuppressive agent. DSG may have a wide potential utility in islet transplantation but it appears to have its strongest effect in islet xenografting.

Vasoactive intestinal peptide suppresses migrating myoelectric complex of rat small intestine independent of nitric oxide.

The involvement of nitric oxide (NO) in the biological response to vasoactive intestinal peptide (VIP) on the migrating myoelectric complex (MMC) of small bowel and systemic arterial blood pressure was investigated in the rat. Animals were supplied with bipolar electrodes for electromyography of the small intestine and blood pressure was assessed by a pressure transducer connected to a carotid artery. In the first session, Nomega-nitro-L-arginine (L-NNA) was administered intravenously at 1, 2, 4 and 20 mg kg(-1). Effects of L-NNA at 1 and 20 mg kg(-1) were also studied after L-arginine 300 mg kg(-1). In the second session, intravenous infusion of VIP 500 pmol kg(-1) min(-1) was administered before and after L-NNA at 1 and 20 mg kg(-1). L-NNA at increasing doses stimulated myoelectric spiking of the small bowel until at 4 mg kg(-1) the MMC was disrupted and irregular spiking induced. Neither at 1 nor 20 mg kg(-1) did L-NNA affect the inhibitory motility response or decrease of blood pressure induced by VIP at a dose of 500 pmol kg(-1) min(-1). Our results show that effects of VIP on motility of the small intestine and systemic arterial blood pressure are direct and not dependent on NO as a common final link.

Low-grade dysplasia in extensive, long-standing inflammatory bowel disease: a follow-up study.

PURPOSE: Extensive, long-standing inflammatory bowel disease is associated with an increased risk of developing colorectal carcinoma. Low-grade dysplasia has been used as a marker for malignant transformation and by some as an indication for prophylactic colectomy. The aim of the present study was to follow up all inflammatory bowel disease patients with extensive, long-standing colitis who had low-grade dysplasia in flat colonic mucosa. METHODS: All patients with low-grade dysplasia in flat mucosa found at screening or at surveillance colonoscopy with at least one follow-up colonoscopy or with colectomy were included. RESULTS: Sixty patients (40 males; mean age at diagnosis, 24 +/- 12 (range, 3-59) years) were found and followed up for a mean of 10 +/- 6 (range, 1-22) years. Mean time from onset of disease to discovery of low-grade dysplasia was 17 +/- 11 (range, 1-55) years. Low-grade dysplasia was present in more than 1 biopsy in 37 (62 percent) of 60 patients at the index colonoscopy. Low-grade dysplasia was again detected in 1.8 (1-6) subsequent colonoscopies in 44 (73 percent) of 60 patients. High-grade dysplasia was found in 2 of 11 patients with dysplasia-associated lesion or mass at follow-up. Thirteen patients were subjected to colectomy (7 for dysplasia, 6 for therapy failure). Dysplasia was confirmed in five of these patients. CONCLUSION: Although low-grade dysplasia occurred at several colonic levels and at repeated colonoscopies in 73 percent of the patients, no progression to high-grade dysplasia was found during 10 years of follow-up, except in 2 cases with dysplasia-associated lesion or mass. Colectomy in cases with single or repeated low-grade dysplasia in flat mucosa does not appear to be justified.

Beneficial effects of ropivacaine in rat experimental colitis.

Ropivacaine, a new, long-acting local anesthetic agent, has been shown to have beneficial effects in the treatment of ulcerative colitis. Treatment with this drug results in prompt symptomatic relief. The aim of this study was to examine the effects of ropivacaine on mucosal healing and to investigate whether ropivacaine can restore the decreased colonic contractility seen in the diseased state. Colitis was induced in rats by a single intrarectal administration of trinitrobenzene sulfonic acid. Mucosal healing was assessed after 1 week of therapy. The effects on colonic contractility were examined either after 1 week of treatment or by application of the drugs to untreated, inflamed rat colon segments placed in organ baths. After the induction of colitis, daily intracolonic treatment with ropivacaine for 1 week reduced morphological damage and myeloperoxidase activity. One week of treatment also restored the contractile response to acetylcholine. By adding ropivacaine directly to untreated inflamed colonic segments in organ baths, the contractile response to acetylcholine was increased compared with controls. For comparison, the effects of budesonide and 5-aminosalicylic acid were also examined. Ropivacaine improved mucosal healing and restored colonic motor activity in experimental colitis, similar to budesonide but superior to 5-aminosalicylic acid.

Pyoderma gangrenosum associated with crohn disease: effect of TNF-alpha blockade with infliximab.

Eight patients with pyoderma gangrenosum associated with Crohn disease were treated with infliximab. All had active mucosal inflammation indicated by endoscopic examination. Within 1-4 months, infliximab treatment resulted in complete healing of the pyoderma gangrenosum in 3 cases (1 parastomal, 2 lower limb), partial healing in 3 (2 parastomal, 1 lower limb) and temporary improvement in 2. Adverse effects such as skin rash, pneumonia and diarrhoea were seen in three patients. Our results imply that infliximab has a therapeutic potential on skin manifestations associated with inflammatory bowel disease, even though successful treatment may require repeat courses of infliximab infusions.

Rise in morning saliva cortisol is associated with abdominal obesity in men: a preliminary report.

An abnormal regulation of the hypothalamic-pituitary-adrenal (HPA) axis is associated with risk factors for cardiovascular disease and Type 2 diabetes mellitus. The objective of this study was to examine if morning saliva cortisols show similar associations. Twenty-eight men, all 53 yr of age, delivered during an ordinary working day saliva cortisol samples immediately upon awakening and 15 min thereafter as well as at different times during the day, including after a standardized lunch. Dexamethasone (0.5 mg) suppression of cortisol was also measured. The rise of morning cortisol values was positively associated with body mass index (r: 0.45, p=0.016), waist/hip ratio (r: 0.54, p=0.003), abdominal sagittal diameter (r: 0.54, p=0.003), glucose (r: 0.54, p=0.003), insulin (r: 0.57, p=0.002) and triglycerides (r: 0.46, p=0.014). The morning rise also correlated positively with the elevation of cortisol following lunch (r: 0.45, p=0.043) but not with other cortisol measurements or dexamethasone suppression. Elevation of cortisol immediately after awakening has previously been found to provide a simple indicator of HPA axis regulation, as suggested also by the results of this study, and an elevated rise has been reported after exposure to frequent or chronic perceived stress. The rise of cortisol immediately after awakening might be an indicator of an increased risk of developing serious, prevalent diseases via the metabolic syndrome.

Inhibition of cortisol secretion by dexamethasone in relation to body fat distribution: a dose-response study.

There is now evidence of a hypersensitive hypothalamo-pituitary-adrenal (HPA) axis in subjects with an elevated waist/hip circumference ratio (WHR), an indicator of the centralization of body fat stores. The activity of the HPA axis is regulated by central glucocorticoid receptors, whose activity can be tested by the administration of exogenous glucocorticoids, which normally inhibit cortisol secretion. In this study, dexamethasone (dex) was administered in random order in doses of 0.05, 0.125, 0.25 and 0.5 mg at 10 p.m. with measurements of serum cortisol in the morning (8 a.m.) of this and the following day. The test was performed on 22 apparently healthy men, 40 to 60 years of age, recruited from laboratory personnel, outpatient clinics or advertisements in a newspaper. Eight had a body mass index (BMI) (kg/m2) of < 25 and 14 of > 25. Twelve men had a waist hip ratio (WHR) of < 1.0 and 10 men had a WHR of > 1.0. Cortisol values at baseline were correlated inversely with WHR and were usually lower in men with a high (> 1.0) rather than a low than low (< 1.0) WHR after dex inhibition. There was apparently no inhibition by dex at 0.05 and 0.125 mg on average in men with a WHR of > 1.0. In addition, the inhibition at 0.5 mg dex correlated negatively with the WHR and was significantly lower (p < 0.05) in men with a WHR of > 1.0 than in men with a WHR of < 1.0. None of these differences or relationships was found to be dependent on BMI. It is concluded that men with an elevated WHR experience a decrease in the inhibition of cortisol secretion by dex. It is suggested that this could explain or contribute to the elevated sensitivity of their HPA axis. Furthermore, lower morning cortisol concentrations suggest a change in diurnal secretion patterns.

Urinary albumin excretion and heart rate variability in obese women.

OBJECTIVE: The aim of this work was to examine the relationship between cardiac autonomic function and urinary albumin excretion in obesity. SUBJECTS: These were 27 obese non-diabetic postmenopausal women and 18 non-obese healthy postmenopausal women. MEASUREMENTS: Urinary albumin excretion as well as plasma nitrate, both indices of capillary function, were measured. Power spectral analysis of heart rate variability was performed, as a measurement of vagal function. An oral glucose tolerance test (OGTT) was performed and blood lipids were analysed. RESULTS: The obese women were characterized by higher fasting insulin, sum of glucose, triglycerides and lower high density lipoprotein cholesterol (HDL), the latter of borderline significance, than controls. Urinary albumin excretion (UAE), plasma nitrate and heart rate variability were not different between obese and control women. However, in obese women log UAE correlated positively with systolic and diastolic blood pressure, and inversely with heart rate variability, the latter independent of body mass index (BMI) and the waist/hip circumference ratio. CONCLUSION: It was concluded that this inverse association between UAE and parasympathetic activity in obese women may be an early sign of derangements of endothelial function and autonomic nervous system control, which may contribute to the increased risk of cardiovascular mortality in abdominal obesity.

Endotoxin actions on myoelectric activity, transit, and neuropeptides in the gut. Role of nitric oxide.

The lipopolysaccharide (endotoxin) of gram-negative bacteria has systemic effects in animals and man. Our aim was to investigate the effects of E. coli lipopolysaccharide on motility and transit through the small intestine in rats and to analyze plasma and tissue concentrations of intestinal neuropeptides. When lipopolysaccharide (20-160 micrograms/kg) was administered intravenously, the migrating myoelectric complex was replaced by spike bursts accompanied by rapid transit. Tissue concentrations of substance P and neurokinin A decreased, while plasma levels of calcitonin gene-related peptide increased N omega-Nitro-L-arginine, N omega-L-arginine methyl ester, dexamethasone, or indomethacin prevented these changes in myoelectric activity and tissue contents of neuropeptides. All of these compounds, except indomethacin, prevented the increased rate of transit. Thus, lipopolysaccharide changes motility through the nitric oxide and arachidonic pathways, resulting in rapid transit through the gut.

Pelvic reservoir with S-pouch: can surgeons evaluate the results of their own operations?

PURPOSE: This study was designed to evaluate whether operating surgeons could follow up the functional outcome of their own operations, without bias, by using standardized methods at follow-up. METHODS: Fifty-five patients who received a pelvic reservoir with an S-pouch were evaluated regarding functional outcome after at least one year postoperative follow-up. The functional surgical outcome was evaluated by an internist especially trained in gastroenterology and the operating surgeon by using a standardized scale comprising eight functional variables. RESULTS: None of the variables analyzed reached statistically significant difference between the two observers, and a high degree of agreement could be shown by using kappa and weighted kappa analysis. CONCLUSIONS: Our results indicate that it is possible for an operating surgeon to assess the postoperative surgical outcome using standardized methods at follow-up.