Neural Correlates of Suicidal Ideation and Its Reduction in Depression

Background:

The neural correlates of suicidal ideation and its reduction after treatment are unknown. We hypothesized that increased regional cerebral glucose metabolism in the infralimbic cortex (Brodmann area 25), amygdala, and subgenual anterior cingulate cortex would be associated with suicidal ideation and its reduction after ketamine infusion.

Methods:

Medication-free patients (n=19) with treatment-resistant major depressive disorder underwent positron emission tomography imaging at baseline and 230 minutes after an open-label ketamine infusion (0.5mg/kg for 40 minutes).

Results:

Baseline suicidal ideation and regional cerebral glucose metabolism in the infralimbic cortex were significantly correlated (r=.59, P=.007); but not overall mood scores (r=−.07, P=.79). Reductions in suicidal ideation after ketamine infusion were correlated with decreased regional cerebral glucose metabolism in the infralimbic cortex (r=.54, P=.02). Metabolism in other areas of interest was not significantly correlated with suicidal ideation or depression.

Conclusion:

The infralimbic cortex may be implicated in suicidal ideation.     

Pediatric solid organ transplant recipients: Transition to home and chronic illness care

Pediatric SOT recipients are medically fragile and present with complex care issues requiring high‐level management at home. Parents of hospitalized children have reported inadequate preparation for discharge, resulting in problems transitioning from hospital to home and independently self‐managing their child's complex care needs. The aim of this study was to investigate factors associated with the transition from hospital to home and chronic illness care for parents of heart, kidney, liver, lung, or multivisceral recipients. Fifty‐one parents from five pediatric transplant centers completed questionnaires on the day of hospital discharge and telephone interviews at three wk, three months, and six months following discharge from the hospital. Care coordination (p = 0.02) and quality of discharge teaching (p < 0.01) was significantly associated with parent readiness for discharge. Readiness for hospital discharge was subsequently significantly associated with post‐discharge coping difficulty (p = 0.02) at three wk, adherence with medication administration (p = 0.03) at three months, and post‐discharge coping difficulty (p = 0.04) and family management (p = 0.02) at six months post‐discharge. The results underscore the important aspect of education and care coordination in preparing patients and families to successfully self‐manage after hospital discharge. Assessing parental readiness for hospital discharge is another critical component for identifying risk of difficulties in managing post‐discharge care.     

Human platelet signaling defect characterized by impaired production of inositol-1,4,5-triphosphate and phosphatidic acid and diminished Pleckstrin phosphorylation: evidence for defective phospholipase C activation

Signal transduction on platelet activation involves phosphoinositide- specific phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositides and formation of inositol-1,4,5-triphosphate [I(1,4,5)P3], which mediates Ca2+ mobilization, and diacylglycerol (DG), which activates protein kinase C (PKC) to phosphorylate a 47-kD protein (Pleckstrin). We studied these events in two related patients previously reported (Blood 74:664, 1989) to have abnormal aggregation and 14C-serotonin secretion, and impaired intracellular Ca2+ mobilization in response to several agonists. Thrombin-induced I(1,4,5)P3 and phosphatidic acid formation were diminished. Pleckstrin phosphorylation was impaired on activation with thrombin, platelet- activating factor, and ionophore A23187, but was normal with PKC activator 1,2-dioctonyl-sn-glycerol (DiC8). Ca2+ mobilization induced by guanosine triphosphate (GTP) analog guanosine 5'-0-(3 thiotriphosphate) (GTP gamma S) was diminished. Pretreatment with either A23187 or DiC8 did not correct the impaired adenine diphosphate- induced secretion; however, upon stimulation with A23187 plus DiC8, pleckstrin phosphorylation and secretion were normal, indicating that both PKC activation and Ca2+ mobilization are essential for normal secretion. We conclude that these patients have a unique inherited platelet defect in formation of two key intracellular mediators [I(1,4,5)P3 and DG] and in the responses mediated by them due to a defect in postreceptor mechanisms of PLC activation.     

Tissue prostaglandin levels in familial adenomatous polyposis patients treated with sulindac

BACKGROUND: Recent work has demonstrated a correlation between frequency of aspirin ingestion and colorectal cancer prevention. Sulindac, another nonsteroidal anti-inflammatory drug (NSAID), has been shown to cause polyp regression and a fall in cell proliferation in patients with familial adenomatous polyposis, who are destined to develop colorectal cancer unless the colon is removed. However, the mode of action of NSAIDs in colorectal carcinogenesis prevention remains to be determined, although a prostaglandin-mediated mechanism seems likely. METHODS: Rectal or duodenal biopsies from 20 patients with familial adenomatous polyposis, who had been randomized to sulindac or placebo, were analyzed for prostaglandin (PG) E₂ and E_2α levels before and after treatment. RESULTS: A significant fall in prostaglandin E₂ and E_2α (P=0.0096; PGE₂, P=0.036; PGF_2α Spearman's rank correlation). CONCLUSIONS: Nonsteroidal antiinflammatory drugs may prevent colorectal cancer by their inhibition of prostaglandin synthesis. Prostaglandins may be implicated in carcinogenesis through an increase in cell proliferation, through immunosuppression, by increasing neovascularization, or via a mutagenic effect.     

Rofecoxib as adjunctive therapy for haemophilic arthropathy

Joint haemorrhage and subsequent haemophilic arthropathy are significant complications in haemophilia. The pathophysiology involves inflammation and angiogenesis. Cyclooxygenase-2 (COX-2) inhibitors are anti-inflammatory agents, which have potent anti-inflammatory, anti-angiogenic and analgesic properties yet do not affect platelet function in the manner of traditional non-steroidal anti-inflammatory drugs. These properties make such agents potentially useful as adjunctive therapy in haemophilia. There is only one prior report describing rofecoxib treatment in a single haemophilia patient. Our objectives were to determine the safety and efficacy of rofecoxib in treating acute haemarthrosis, chronic synovitis, target joints and pain. We conducted a retrospective medical record review of patients treated with rofecoxib for acute haemarthrosis, chronic synovitis, target joint or pain. The safety and efficacy of rofecoxib treatment were determined based on subjective patient reports and physical examinations during follow-up clinic visits. A total of 28 patients between 3 and 37 years of age were treated for a total of 42 courses of rofecoxib treatment. All courses were evaluated for safety and 31 for efficacy. Rofecoxib was used for eight acute haemarthrosis, four target joints, seven cases of synovitis and 12 episodes of pain. Efficacy was demonstrated particularly for chronic synovitis and pain and no serious adverse events occurred. This is the largest study to date evaluating COX-2 inhibitors as adjunctive therapy in haemophilia and suggests that these agents may be an important adjunctive therapy in the management of haemophilia.     

Old age security and the defense of social norms

This paper identifies various kinds of risk and uncertainty observable in rural areas of developing countries and explains the relative importance of those pertaining to disability and old age. It compares the modern system (based on old age pensions and social security) for mitigating or coping with these risks with the traditional intrafamilial support mechanisms. The paper concludes that, when the traditional system is functioning smoothly, it can address these needs at far lower cost than the modern system. The efficiency and viability of the traditional system can be considerably enhanced by the presence of social norms, on the one hand, and of strategic instruments in the hands of household heads, on the other. Since both of these defenses are often undermined prematurely by modernizing influences, the paper identifies possible actions for avoiding or postponing the effects of such influences.The author expresses his appreciation to Richard Anker, Mussadegh Chowdhury, Richard Easterlin, Jeremy Evans and one of the editors for useful comments and suggestions and to the US Agency for International Development for financial support for some earlier research upon which this paper is partially based.     

Acquired granular pool defect in stored platelets

Platelets stored as concentrates (PC) for 72 h at 22 degrees C develop a functional defect. Alterations in adenine nucleotides of platelets have been shown to affect platelet function. Adenine nucleotide content of platelets was measured before and after storage and a decrease of 27.1 /+- 1.7% (mean /+- SE) in ATP and 39.1 /+- 2.6% in ADP were found in 34 PC stored with final volume of 50 ml. In 11 PC with 30 ml volume. ATP and ADP decreased by 39.4 /+- 3.2% and 49.4 /+- 2.1%, respectively. The mean ATP to ADP ratio of stored platelets was significantly higher than of fresh platelets in both groups, suggesting a relatively greater decrease in granular than metabolic pool nucleotides. Levels of low affinity platelet factor 4 measured by radioimmunoassay in plasma from 0.86 /+- 0.08 microgram/ml in the fresh PC to 8.59 /+- 0.39 microgram/ml in stored PC, indicating a concomitant alpha-granular secretion. Labeling of metabolic pool with 14C-adenine revealed a mean decrease in the adenylate energy charge of 2.0 /+- 0.4% in 12 of 16 stored PC, with a lower ATP and higher hypoxanthine labeling in stored as compared to fresh platelets. These observations suggest that stored platelets develop an acquired defect in both dense and alpha granules and in their ability to maintain ATP homeostasis.     

Modulation by progestogens of the effects of oestrogen on hepatic endocrine function in postmenopausal women

OBJECTIVE: Oral but not transdermal oestrogen administration reduces IGF-I, and increases GH binding protein (GHBP) reflecting effects on hepatic endocrine function in postmenopausal women. As progestogens attenuate the effects of oestrogen on circulating lipid levels according to their androgenic properties, we have investigated the impact of progestogen types on the hepatic endocrine effects of oestrogen. DESIGN: Four progestogens differing in androgenicity were co-administered in a monthly cyclical regimen in random order to postmenopausal women receiving either oral (n = 9, premarin 1.25 mg) or transdermal (n = 10, Estraderm 100 microg patches twice weekly). The four progestogens were cyproterone acetate (CA 5 mg, antiandrogenic), dydrogesterone (20 mg, neutral), medroxyprogesterone acetate (MPA 10 mg, mildly androgenic), norethisterone (2.5 mg, androgenic). PATIENTS: Nineteen postmenopausal women (age 57 +/- 3 years, mean +/- SE) were studied. MEASUREMENTS: The effects of oestrogen alone and the combined effects with each progestogen type on IGF-I, GHBP, SHBG, cholesterol, triglycerides and lipoprotein(a) were investigated. RESULTS: Mean IGF-I fell while GHBP and SHBG levels increased with oral (P < 0.01) but not transdermal oestrogen administration. When the combined effects were examined, progestogens did not affect IGF-I, GHBP and SHBG during oral oestrogen treatment, while they significantly increased (P < 0.01) mean IGF-I levels during transdermal therapy. Among the progestogen types, only norethisterone prevented the fall in IGF-I induced by oral oestrogen. During transdermal therapy, MPA and norethisterone but not CA or dydrogesterone significantly increased (P < 0.005) IGF-I. The rise in GHBP induced by oral oestrogens tended to be lower during co-administration of MPA and norethisterone. The increase in SHBG induced by oral oestrogen was attenuated (P < 0.05) by norethisterone which was the only progestogen that lowered SHBG (P < 0.05) during transdermal oestrogen treatment. Mean IGF-I was higher (P < 0.001), GHBP and SHBG lower during co-administration of androgenic progestogens (MPA and norethisterone). CONCLUSIONS: Oestrogen effects on IGF-I, GHBP and SHBG are dependent on the route of administration with progestogens having variable effects. Among the progestogen types, norethisterone, the most androgenic, had the greatest effect, particularly on IGF-I. Progestogens modulate the effects of oestrogen on hepatic endocrine function in relation to their intrinsic androgenic properties. The modulatory effects of progestogens on IGF-I during oestrogen therapy may have long-term implications for lean body mass.     

A human monoclonal autoantibody recognizes a neoantigen on glycoprotein IIIa expressed on stored and activated platelets

We prepared a heterohybrid cell line that secretes a human IgM monoclonal autoantibody that recognizes an antigen found on thrombin-activated or stored platelets. The surface expression of the epitope recognized by this autoantibody, 5E5, increases with time as platelets age in vitro, suggesting that it may represent a senescence or activation-specific antigen. 5E5 binds to the purified platelet membrane glycoprotein (GP) IIb-IIIa complex in an enzyme-linked immunosorbent assay (ELISA). In an immunoblot technique, 5E5 binds to a protein with an apparent mol wt of 95,000, which is identical to that of GPIIIa under nonreduced conditions. In crossed immunoelectrophoresis (CIE), the predominant antigen recognized by 5E5 is contained in the GPIIb-IIIa precipitin arc. An additional precipitin arc recognized by 5E5 is often observed only on gels derived from lysates of platelets stored under blood bank conditions for greater than 3 days. These findings illustrate the usefulness of human monoclonal antibodies for the identification of membrane neoantigens expressed as a result of platelet activation or revealed as platelets age in vitro.