Does early-onset chronic or recurrent major depression impact outcomes with antidepressant medications? A CO-MED trial report.

BACKGROUND: Prior studies have suggested that major depressive disorder (MDD) with pre-adult onset represents a distinct subtype with greater symptom severity and higher rates of suicidal ideation. Whether these patients have poorer response to various types of antidepressant treatment than those with adult-onset MDD is unclear. Method A total of 665 psychiatric and primary care out-patients (aged 18-75 years) with non-psychotic chronic or recurrent MDD participated in a single-blind, randomized trial that compared the efficacy of escitalopram plus placebo, bupropion sustained-release plus escitalopram, or venlafaxine extended-release plus mirtazapine. We compared participants who self-reported MDD onset (before age 18) to those with a later onset (adult onset) with respect to baseline characteristics and treatment/outcome variables at 12 and 28 weeks. RESULTS: Early-onset chronic/recurrent MDD was associated with a distinct set of sociodemographic (female, younger age) and clinical correlates (longer duration of illness, greater number of prior episodes, greater likelihood of atypical features, higher rates of suicidality and psychiatric co-morbidity, fewer medical problems, poorer quality of life, greater history of child abuse/neglect). However, results from unadjusted and adjusted analyses showed no significant differences in response, remission, tolerability of medications, quality of life, or retention at 12 or 28 weeks. CONCLUSIONS: Although early-onset chronic/recurrent MDD is associated with a more severe clinical picture, it does not seem to be useful for predicting differential treatment response to antidepressant medication. Clinicians should remain alert to an increased risk of suicidality in this population.

Is prior course of illness relevant to acute or longer-term outcomes in depressed out-patients? A STAR*D report.

BACKGROUND: Major depressive disorder (MDD) is commonly chronic and/or recurrent. We aimed to determine whether a chronic and/or recurrent course of MDD is associated with acute and longer-term MDD treatment outcomes. METHOD: This cohort study recruited out-patients aged 18-75 years with non-psychotic MDD from 18 primary and 23 psychiatric care clinics across the USA. Participants were grouped as: chronic (index episode >2 years) and recurrent (n = 398); chronic non-recurrent (n=257); non-chronic recurrent (n=1614); and non-chronic non-recurrent (n = 387). Acute treatment was up to 14 weeks of citalopram (≤ 60 mg/day) with up to 12 months of follow-up treatment. The primary outcomes for this report were remission [16-item Quick Inventory of Depressive Symptomatology - Self-Rated (QIDS-SR(16)) ≤ 5] or response (≥ 50% reduction from baseline in QIDS-SR(16)) and time to first relapse [first QIDS-SR16 by Interactive Voice Response (IVR) ≥ 11]. RESULTS: Most participants (85%) had a chronic and/or recurrent course; 15% had both. Chronic index episode was associated with greater sociodemographic disadvantage. Recurrent course was associated with earlier age of onset and greater family histories of depression and substance abuse. Remission rates were lowest and slowest for those with chronic index episodes. For participants in remission entering follow-up, relapse was most likely for the chronic and recurrent group, and least likely for the non-chronic, non-recurrent group. For participants not in remission when entering follow-up, prior course was unrelated to relapse. CONCLUSIONS: Recurrent MDD is the norm for out-patients, of whom 15% also have a chronic index episode. Chronic and recurrent course of MDD may be useful in predicting acute and long-term MDD treatment outcomes.

Simplified retrograde systemic perfusion for removal of air from the aorta in an infant.

Total circulatory arrest with full venous drainage can result in air entering the arterial system through several possible sites such as the aortic cannulation site or collateral vessels. Air present in the arterial system during total circulatory arrest imposes a special problem. We describe a simple technique of short-term retrograde systemic perfusion to remove air from the arterial system before restarting systemic arterial perfusion after total circulatory arrest.

Revascularization of the ischemic colon transplant using the internal mammary vessels.

We describe a successful reconstruction of the esophagus with the isoperistaltic right colon and terminal ileum, which had very poor continuity of the marginal artery. The stomach and the left colon were not available because of corrosive injury and intraabdominal adhesions. The blood supply of the ischemic transplant was augmented by anastomosis of the internal mammary vessels to the iliocolic vessels.

Permanent neurologic deficits in heat stroke.

Heat stroke rarely develops permanent neurologic deficits. We present two patients (patients 1 and 2) who suffered from persistent neurologic deficits 3 years after heat stroke. Both patients have cerebellar dysfunction. In addition to cerebellar dysfunction, the first patient whose CT scan of brain demonstrates cerebellar atrophy, also has signs of transverse myelopathy of thoracic cord. We conclude the cerebellar symptoms are common neurologic complication of heat stroke and the heat stroke may be one of rare causes of the transverse myelopathy.

Essential tremor: clinical, electromyographical and pharmacological studies in 146 Chinese patients.

From February 1984 to February 1988, 258 cases of various kinds of tremor were seen in our movement disorder clinic. Among them, 146 cases (57%) were diagnosed as essential tremor, and of these, 96 (65.8%) were males and 50 (34.2%) were females, ranging in age from 14 to 89 years (mean: 36 years). The main tremor occurred in the hands (100%), and in a few cases were combined with head, leg, lip, voice and neck tremors. A familial tendency was obvious in 47 cases (32%). The surface electromyographic (EMG) study of essential tremor revealed two patterns, one of synchronous type (73%) and the other of alternating type (27%). Its frequency was between 5 and 9Hz. The burst duration was short (50-100 msec) and the amplitude was low (less than 200 mu v). All cases were divided into two groups to received propranolol therapy, 78 cases with high dosages (120-240 mg/day) and 68 with low dosages (60-80 mg/day). The higher dose was better in effect than the lower one (p less than 0.01). Propranolol also had effect on tremors of alternating type (p less than 0.01), which is different from previous reports.

Intracellular distribution of molecular forms of acetylcholinesterase in rat brain and changes after diisopropylfluorophosphate treatment.

The subcellular distribution of acetylcholinesterase activities was studied in the striatum and cerebellum of rat brain. The highest percentage of the enzyme activity was found in the crude synaptosomal (P2) fraction, with striatum much higher than cerebellum. On sucrose density gradient centrifugation analyses all the particulate fractions (P1, P2, and P3) showed a major peak of the 10 S form of acetylcholinesterase activity with very little activity of the 4 S form of the enzyme. The 10 S/4 ratio was much higher in striatum than in cerebellum. In the soluble fraction (100,000 g supernatant) the 10 S form was less than the 4 S form in the adult rat brain, but this was reversed in the 6-day-old rat brain. After diisopropylfluorophosphate administration the recovery of acetylcholinesterase molecular forms in various subcellular fractions differed at different recovery periods. These results indicate that the distribution of molecular forms of acetylcholinesterase in rat brain differs in various subcellular fractions, and also the pattern of distribution differs in different regions of the brain as well as in adult and developing brains.

Interaction of a water-soluble derivative of delta-9-tetrahydrocannabinol with [3H]diazepam and [3H]flunitrazepam binding to rat brain membranes.

We have tested the effect of a psychoactive water-soluble derivative of delta-9-tetrahydrocannabinol, SP-111A, on the binding of [3H]diazepam and [3H]flunitrazepam to rat brain membranes. It was found that SP-111A reduced the specific binding of [3H]diazepam and [3H]flunitrazepam. The inhibition by SP-111A was dependent not only on the concentration of the ligand but also on the protein content of membrane preparations. The inhibition of the specific binding of [3H]diazepam by SP-111A was found to be competitive with Ki value of 3.1 microM. In the presence of 7.5 microM SP111A the apparent Kd of [3H]diazepam binding increased from 4.3 nM to 12.5 nM, without affecting the Bmax. The inhibition of the specific binding of [3H]flunitrazepam by SP-111A was also competitive, however, the IC50 was higher than with [3H]diazepam. The inhibition by SP-111A appeared to be caused by its tight binding to the benzodiazepine binding sites of brain membranes.

Immunohistochemical co-localization of S-100b and the glial fibrillary acidic protein in rat brain.

A rabbit antiserum against purified bovine brain S-100b protein was produced and characterized by immunoassay and immunoblot analysis of electrophoretically resolved soluble brain proteins. Fluorescent immunohistochemistry was conducted in order to determine the cellular localization of the S-100b immunoreactivity. Double immunohistofluorescent experiments on adult rat brain tissue sections with the rabbit antiserum to S-100b and a rat monoclonal antibody to the glial fibrillary acidic protein resulted in immunolabelling of the same cells. This finding determines a strict astroglial localization of the S-100b immunoreactivity. In addition, the immunolabelling of astrocyte perikarya and processes by the S-100b immunohistochemistry is consistent with a cytoplasmic location of S-100b. In contrast, the glial fibrillary acidic protein immunohistochemistry predominantly labeled the fine fibrillary processes of the cells. The present report suggests that S-100b immunohistochemistry is of use for the specific identification and morphological description of astrocytes in the rat brain.

Effects of various 2-amino-6-alkyldithiopurines on brain specific [3H]diazepam binding.

Various derivatives of 2-amino-6- methylthiopurine with substituents at the 6-position of purine were tested for their abilities to displace [3H]diazepam binding to rat brain membranes. The potency was dependent on the carbon chain-length in the 6-position of purine. Among the derivatives tested, 2-amino-6-n- pentyldithiopurine had the highest potency, with a Ki value of 0.92 microM.

Molecular forms of sucrose extractable and particulate acetylcholinesterase in the developing and adult rat brain.

The activity of acetylcholinesterase in the rat striatum increased considerably during development, while activities in the cerebellum and midbrain increased only slightly. During maturation the activity of butyrylcholinesterase increased in all the brain regions examined except in cerebellum. The percentage of acetylcholinesterase extractable by isotonic sucrose solution from mature striatum was much smaller than those obtained for other regions of the rat brain. For the developing striatum, the percentage of isotonic sucrose extractable activity was almost three times that for adult striatum. Density gradient centrifugation showed that the membrane-bound particulate fraction of adult rat brain was mostly composed of the 10 S form of acetylcholinesterase with little activity of 4 S form of the enzyme. However, a much higher proportion of the 4S form was found in the isotonic sucrose soluble fraction. In contrast to the particulate fraction from adult brain, that from 6-day old rats contained a much higher proportion of the 4 S form of the enzyme. The sucrose soluble fraction from 6-day old rat brains contained in general much smaller proportion of 4S form as compared to those from adult rat brains.

Effect of synthetic purines and purine nucleosides on [3H]diazepam binding in brain.

We have compared fifteen synthetic purines and purine nucleosides on their ability to displace [3H]diazepam binding to rat brain membranes. Among these analogs, 6-methylthioguanine was found to be most potent, inhibiting competitively the specific binding of [3H]diazepam with a Ki value of 16 micro M. At a concentration of 50 micro M, 6-methyl-thioguanine increased tha apparent Kd of specific diazepam binding from 4.3 nM to 13.3 nM without affecting the Bmax, nor had it any effect on the non-specific binding. Binding with membrane preparations from developing rat brain was slightly less sensitive to 6-methylthioguanine inhibition than that with membranes prepared from mature brain.

Acetylcholinesterase and butyrylcholinesterase released from normal and dystrophic muscles by treatment with proteolytic enzymes.

1. Skeletal muscle from C57BL dystrophic mice demonstrated decreased activities of acetylcholinesterase with increased activities of butyrylcholinesterase. These changes were less distinct when compared to those observed with 129 ReJ mice. 2. Collagenase or trypsin treatment solubilized less acetylcholinesterase activity but more butyrylcholinesterase activity from muscle of C57BL dystrophic mice than from muscle of control mice. 3. These treatments resulted in similar pattern of release of acetylcholinesterase activity from muscle of 129 ReJ mice, except that more acetylcholinesterase activity was released from dystrophic muscle (129 ReJ) than from control by pepsin treatment. 4. The acetylcholinesterase activities released by proteolytic enzymes were characterized by sucrose density gradient centrifugation.

Purification of chicken brain choline acetyltransferase.

Chicken brain choline acetyltransferase was purified to homogeneity using ammonium sulfate fractionation, followed by chromatography on DEAE-Sephadex (A-25), hydroxyapatite, Sephadex G-150, immunoabsorption and Sepharose-CoA columns. A purification of 3500-fold was achieved and the final preparation had a specific activity of 2:32 ?mol acetylcholine formed per minute per milligram protein. The purified chicken choline acetyltransferase migrated as a single band on polyacrylamide gel electrophoresis in the presence and absence of sodium deodecyl sulfate. The native enzyme, with a molecular weight of 67,000 daltons, consists of two subunits of identical molecular weight. Chicken choline acetyltransferase has a sharp pH optimum of 7.4. It is activated by sodium chloride and potassium chloride but inhibited by cupric ion and N-ethylmaleimide.

Purification and immunochemical properties of choline acetyltransferase from human brain.

Choline acetyltransferase (CAT) was purified to homogeneity from 363 g of human neostriatum by means of ammonium sulfate and protamine sulfate fractionation, followed by chromatography on DEAE-Sephadex, hydroxyapatite, phosphocellulose, and agarose-hexane-Co A columns. The final product migrated as a single component on 7.5% gels with or without SDS. It had a molecular weight of 66,000 daltons and a specific activity of 7.3 mumol acetylcholine formed per milligram protein per minute. Antibodies prepared in rabbits gave single precipitin lines against this protein on Ouchterlony immunodiffusion and immunoelectrophoresis plates. The CAT-anti-CAT IgG complex migrated as a single band on gel electrophoresis, establishing the monospecificity of the antibodies. Strong cross-reactivity to the IgG was obtained with CAT from rat, rabbit, and guinea pig, but only weak reactivity with chicken. Fab fragments were prepared from the rabbit IgG and were used to stain CAT-containing neurons in the spinal cord and nerve endings at the neuromuscular junction using the PAP technique.

Collagenase-releasable and -resistant cholinesterases in normal and dystrophic muscles.

The release of acetylcholinesterase activity by collagenase from the particulate fraction of mouse muscle homogenate into the soluble fraction was dependent on the time of incubation of muscle homogenate with collagenase. The collagenase-stimulated release of acetylcholinesterase was inhibited by 1,10-phenanthroline, an inhibitor of collagenase. Differential effects of inhibitors of specific acetylcholinesterase and nonspecific cholinesterase were observed in both collagenase extract and collagenase-resistant fraction derived from homogenate of muscle of normal and dystrophic mice. The collagenase extract of dystrophic muscle contained distinctly lower activity of acetylcholinesterase than that of normal muscle, while both collagenase extract and collagenase-resistant fraction of dystrophic muscle showed much higher activity of butyrylcholinesterase activity than those from normal muscle.

Acetylcholinesterase solubilized from normal and dystrophic muscle by collagenase treatment.

The activity of specific acetylcholinesterase, assayed in the presence of an inhibitor of nonspecific cholinesterase, was significantly lower in the leg muscle of dystrophic mice of Bar Habor strain 129 than in that of normal mice. However, the nonspecific butyrylcholinesterase activity was much higher in dystrophic muscle than in normal muscle. Collegenase released more acetylcholinesterase activity into the soluble fraction derived from homogenized normal muscle than into that derived from dystrophic muscle. The collagenase-released activity in the normal muscle contained about 95% specific acetylcholinesterase while that from dystrophic muscle contained only 74% specific acetylcholinesterase activity. The acetylcholinesterase activity solubilized by collagenase from control muscle contained the highest activity in 10 S form with decreasing activity of 16 S and 4 S forms, but that from dystrophic muscle contained much less of the 16 S and 10 S forms with more 4 S form, compared to the controls.

Cholinergic systems in muscle and brain in vitamin E-deficient rats.

Rats fed a vitamin E-deficient diet for 7--8 weeks postweaning showed no change in brain weight or the activity in brain of various enzymes involved in neurotransmitter synthesis and metabolism. Body and muscle weights were markedly reduced. Muscle choline acetyltransferase and acetylcholinesterase activities were significantly elevated on a protein basis, but the total amount of choline acetyltransferase/muscle was essentially normal and total acetylcholinesterase activity was slightly reduced. Total carnitine acetyltransferase and butyrylcholinesterase activities were markedly decreased. The results are quite different from those found in hereditary murine muscular dystrophy and suggest a myogenic etiology for the vitamin E-deficiency-induced condition.