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Background: While treatment for breast cancer has been refined and overall survival has improved, there is concern that the incidence of brain metastases has increased. Methods: We identified patients in Sweden with incident breast cancer 1998–2006 in the National Cancer Register, and matched these to the National Patient Register to obtain information on hospital admissions for distant metastases. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed with Cox regression as estimates of relative risk. Results: Among 50 528 breast cancer patients, 696 (1.4%) were admitted with brain metastases during median 3.5 years of follow-up. Admissions for other metastases were found in 3470 (6.9%) patients. Compared with the period 1998–2000, patients diagnosed with breast cancer 2004–2006 were at a 44% increased risk of being admitted with brain metastases (HR 1.44, 95% CI 1.13–1.85). Conclusion: The incidence of admissions with brain metastases in breast cancer patients was increasing in the mid-2000s in Sweden. These findings support a true increase in incidence of brain metastases among breast cancer patients.

Elevated cerebrospinal fluid (CSF) levels of the glia-derived N -methyl- D -aspartic acid receptor antagonist kynurenic acid (KYNA) have consistently been implicated in schizophrenia and bipolar disorder. Here, we conducted a genome-wide association study based on CSF KYNA in bipolar disorder and found support for an association with a common variant within 1p21.3. After replication in an independent cohort, we linked this genetic variant—associated with reduced SNX7 expression—to positive psychotic symptoms and executive function deficits in bipolar disorder. A series of post-mortem brain tissue and in vitro experiments suggested SNX7 downregulation to result in a caspase-8-driven activation of interleukin-1β and a subsequent induction of the brain kynurenine pathway. The current study demonstrates the potential of using biomarkers in genetic studies of psychiatric disorders, and may help to identify novel drug targets in bipolar disorder.

Background: Brain metastases (BM) constitute the most common intracranial tumours and are associated with considerable morbidity and mortality. Population-based studies of the epidemiology and time trends of BM are scarce. Methods: A population-based cohort of patients admitted to hospital with BM in Sweden between 1987 and 2006 ( n =15 517) was identified and linked to nationwide registers of cancer incidence and death. Primary cancer types were assessed and time to hospitalisation and death was computed. Results: The annual age-adjusted incidence rate of hospitalisation for BM doubled from 7 to 14 patients per 100 000 between 1987 and 2006. The most common primary tumours among women were lung (33%), breast (33%) and colorectal cancer (7%), and among men lung cancer (44%), malignant melanoma (12%) and colorectal cancer (9%). The increase was most evident for BM patients with lung cancer (both sexes) and breast cancer (women). Survival was short, with a median of 2.7 months. It varied little by cancer type and did not improve over calendar time. Conclusion: The number of patients admitted with BM has increased rapidly in Sweden. In spite of recent improvements in the prognosis of common primary cancer types, any parallel improvement among patients with advanced cancer and BM is not indicated.

We performed a genome-wide association study of 6447 bipolar disorder (BD) cases and 12 639 controls from the International Cohort Collection for Bipolar Disorder (ICCBD). Meta-analysis was performed with prior results from the Psychiatric Genomics Consortium Bipolar Disorder Working Group for a combined sample of 13 902 cases and 19 279 controls. We identified eight genome-wide significant, associated regions, including a novel associated region on chromosome 10 (rs10884920; P =3.28 × 10 −8 ) that includes the brain-enriched cytoskeleton protein adducin 3 ( ADD3), a non-coding RNA, and a neuropeptide-specific aminopeptidase P ( XPNPEP1) . Our large sample size allowed us to test the heritability and genetic correlation of BD subtypes and investigate their genetic overlap with schizophrenia and major depressive disorder. We found a significant difference in heritability of the two most common forms of BD (BD I SNP- h 2 =0.35; BD II SNP- h 2 =0.25; P =0.02). The genetic correlation between BD I and BD II was 0.78, whereas the genetic correlation was 0.97 when BD cohorts containing both types were compared. In addition, we demonstrated a significantly greater load of polygenic risk alleles for schizophrenia and BD in patients with BD I compared with patients with BD II, and a greater load of schizophrenia risk alleles in patients with the bipolar type of schizoaffective disorder compared with patients with either BD I or BD II. These results point to a partial difference in the genetic architecture of BD subtypes as currently defined.

Background:Telomeres are protective DNA-protein complexes at the ends of each chromosome, maintained primarily by the enzyme telomerase. Shortening of the blood leukocyte telomeres is associated with aging, several chronic diseases, and stress, eg, major depression. Hippocampus is pivotal in the regulation of cognition and mood and the main brain region of telomerase activity. Whether there is telomere dysfunction in the hippocampus of depressed subjects is unknown. Lithium, used in the treatment and relapse prevention of mood disorders, was found to protect against leukocyte telomere shortening in humans, but the mechanism has not been elucidated. To answer the questions whether telomeres are shortened and the telomerase activity changed in the hippocampus and whether lithium could reverse the process, we used a genetic model of depression, the Flinders Sensitive Line rat, and treated the animals with lithium.Methods:Telomere length, telomerase reverse transcriptase (Tert) expression, telomerase activity, and putative mediators of telomerase activity were investigated in the hippocampus of these animals.Results:The naïve Flinders Sensitive Line had shorter telomere length, downregulated Tert expression, reduced brain-derived neurotrophic factor levels, and reduced telomerase activity compared with the Flinders Resistant Line controls. Lithium treatment normalized the Tert expression and telomerase activity in the Flinders Sensitive Line and upregulated β-catenin.Conclusion:This is the first report showing telomere dysregulation in hippocampus of a well-defined depression model and restorative effects of lithium treatment. If replicated in other models of mood disorder, the findings will contribute to understanding both the telomere function and the mechanism of lithium action in hippocampus of depressed patients.

The kynurenine pathway metabolite kynurenic acid (KYNA), modulating glutamatergic and cholinergic neurotransmission, is increased in cerebrospinal fluid (CSF) of patients with schizophrenia or bipolar disorder type 1 with psychotic features. KYNA production is critically dependent on kynurenine 3-monooxygenase (KMO). KMO mRNA levels and activity in prefrontal cortex (PFC) are reduced in schizophrenia. We hypothesized that KMO expression in PFC would be reduced in bipolar disorder with psychotic features and that a functional genetic variant of KMO would associate with this disease, CSF KYNA level and KMO expression. KMO mRNA levels were reduced in PFC of bipolar disorder patients with lifetime psychotic features ( P =0.005, n =19) or schizophrenia ( P =0.02, n =36) compared with nonpsychotic patients and controls. KMO genetic association to psychotic features in bipolar disorder type 1 was studied in 493 patients and 1044 controls from Sweden. The KMO Arg 452 allele was associated with psychotic features during manic episodes ( P =0.003). KMO Arg 452 was studied for association to CSF KYNA levels in an independent sample of 55 Swedish patients, and to KMO expression in 717 lymphoblastoid cell lines and 138 hippocampal biopsies. KMO Arg 452 associated with increased levels of CSF KYNA ( P =0.03) and reduced lymphoblastoid and hippocampal KMO expression ( P ⩽0.05). Thus, findings from five independent cohorts suggest that genetic variation in KMO influences the risk for psychotic features in mania of bipolar disorder patients. This provides a possible mechanism for the previous findings of elevated CSF KYNA levels in those bipolar patients with lifetime psychotic features and positive association between KYNA levels and number of manic episodes.

Telomere shortening is a hallmark of aging and has been associated with oxidative stress, inflammation and chronic somatic, as well as psychiatric disorders, including schizophrenia and depression. Additionally, antidepressants have been found to protect against telomere shortening. However, pharmacological telomere studies are lacking in bipolar disorder (BD). Therefore, the objective of this study was to explore telomere length (TL) in patients with BD in the context of lithium treatment. We determined TL by quantitative real-time PCR using peripheral blood leukocytes. Participants were outpatients diagnosed with BD type 1 or 2 ( n =256) and healthy controls ( n =139). Retrospective case–control and case–case study designs were applied. Lithium response (LiR) was scored using the Alda-Scale. Lithium-treated BD patients overall, as well as those on lithium monotherapy, had 35% longer telomeres compared with controls ( P <0.0005, partial η 2 =0.13). TL correlated positively with lithium treatment duration of >30 months ( P =0.031, R 2 =0.13) and was negatively associated with increasing number of depressive episodes ( P <0.007). BD patients responding well to lithium treatment had longer telomeres than those not responding well. This is the first study to report a positive effect of long-term lithium treatment on TL. Importantly, longer TL was also associated with a better LiR in BD patients. These data suggest that lithium exerts a protective effect against telomere shortening especially when therapeutically efficacious. We hypothesize that induction of telomerase activity may be involved in LiR in BD.

Rapid cycling is a severe form of bipolar disorder with an increased rate of episodes that is particularly treatment-responsive to chronotherapy and stable sleep-wake cycles. We hypothesized that the P2RX7 gene would be affected by sleep deprivation and be implicated in rapid cycling. To assess whether P2RX7 expression is affected by total sleep deprivation and if variation in P2RX7 is associated with rapid cycling in bipolar patients. Gene expression analysis in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and case-case and case-control SNP/haplotype association analyses in patients. Healthy volunteers at the sleep research center, University of California, Irvine Medical Center (UCIMC), USA (n = 8) and Swedish outpatients recruited from specialized psychiatric clinics for bipolar disorder, diagnosed with bipolar disorder type 1 (n = 569; rapid cycling: n = 121) and anonymous blood donor controls (n = 1,044). P2RX7 RNA levels were significantly increased during sleep deprivation in PBMCs from healthy volunteers (p = 2.3*10(-9)). The P2RX7 rs2230912 _A allele was more common (OR = 2.2, p = 0.002) and the ACGTTT haplotype in P2RX7 (rs1718119 to rs1621388) containing the protective rs2230912_G allele (OR = 0.45-0.49, p = 0.003-0.005) was less common, among rapid cycling cases compared to non-rapid cycling bipolar patients and blood donor controls. Sleep deprivation increased P2RX7 expression in healthy persons and the putatively low-activity P2RX7 rs2230912 allele A variant was associated with rapid cycling in bipolar disorder. This supports earlier findings of P2RX7 associations to affective disorder and is in agreement with that particularly rapid cycling patients have a more vulnerable diurnal system.