Insecure attachment relations have been theorized to play a significant role in the development of depressogenic modes of adaptation and to thus form a vulnerability factor for the emergence of depressive disorder in children. This study examined security of parent and peer attachment among four groups of early adolescents: clinically depressed, nondepressed psychiatric controls, nonpsychiatric controls, and adolescents with resolved depression. Depressed adolescents reported significantly less secure parent attachment than either of the control groups, and less secure peer attachment than the nonpsychiatric control group. Attachment security of adolescents with resolved depression was on a par with the nonpsychiatric control group. Among all psychiatric patients, security of attachment to parents was negatively correlated with severity of depression according to interview and self-report ratings. Less secure attachment to parents, but generally not to peers, was also related to more maladaptive attributional styles, presence of separation anxiety disorder, and history of suicidal ideation.

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This study explores whether cognitive attributes differentiate depressed children from those with other psychiatric disorders. The subjects were 108 children from 7 to 17 years of age. Forty-seven children were diagnosed as currently depressed, 30 as having had an episode of major depression within the last year (depressed-resolved), and 31 with diagnoses other than depression (nondepressed). The subjects completed the Piers-Harris Children's Self-Concept Scale, the Children's Hopelessness Scale, the Nowicki-Strickland Children's Locus of Control Scale, the Children's Attributional Styles Questionnaire, and the Children's Depression Inventory. The depressed children endorsed significantly lower self-esteem, more hopelessness, a more externalized locus of control, and a more depressive attributional style than the depressed-resolved or the nondepressed children. Thus, a depressive cognitive style can be documented in clinically depressed young people.Depression in children and adolescents has received considerable attention over the past 10 years. Most of these research efforts have focused on diagnostic questions (Cantwell & Carl-

This study compared the blood pressure-lowering effect of ertugliflozin (1, 5, 25 mg), hydrochlorothiazide (HCTZ; 12.5 mg) and placebo in 194 patients with type 2 diabetes mellitus and hypertension for 4 weeks using ambulatory blood pressure monitoring. Endpoints (change from baseline to week 4) were: 24-h mean systolic blood pressure (SBP; primary); daytime, night-time, seated predose SBP, 24-h, daytime, night-time, seated predose diastolic blood pressure, 24-h urinary glucose excretion and fasting plasma glucose (FPG; secondary). Safety and tolerability were monitored. Significant decreases in placebo-corrected 24-h mean SBP (-3.0 to -4.0 mmHg) were recorded for all doses of ertugliflozin (for HCTZ, this was -3.2 mmHg). Daytime, but not night-time SBP was consistently reduced. Ertugliflozin produced dose-dependent significant decreases in FPG and increases in urinary glucose excretion. No notable changes in plasma renin activity or urinary aldosterone were seen. The most common adverse events were urinary tract infection, genital fungal infection, upper respiratory tract infection and musculoskeletal pain.

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Developability considerations should be integrated with lead engineering of antibody drug candidates in interest of their cost effective translations into medicines. To explore feasibility of this imperative, we have performed rational mutagenesis studies on a monoclonal antibody (MAB1) whose development was discontinued owing to manufacturability hurdles. Seven computationally designed variants of MAB1 containing single point (V44K, E59S, E59T and E59Y) and double (V44KE59S, V44KE59T and V44KE59Y) mutations in its light chain were produced in Chinese Hamster Ovary (CHO) cells and purified by using platform processes employed during commercial scale production of monoclonal antibodies. MAB1 and its variants were formulated in the same platform buffer and subjected to a battery of experiments to assess their solution behaviors, and biological activities. Five of the seven (71%) variants of MAB1 demonstrated improved biophysical attributes in multiple experimental testings. Contrary to the commonly expressed reservations about potential biological activity loss upon developability optimizations, the improvements in solution behavior of MAB1 also increased its biological activity up to ~180%. In particular, concentrate-ability and apparent solubility of V44KE59S improved to ~150% and ~160%, respectively. Its diffusion interaction parameter (kD) reduced to 28% and viscosity at ~100 mg/ml decreased to less than half of the corresponding values for MAB1. V44KE59S is also slightly more active and its transfections in CHO cells were more productive. It also degraded slower than MAB1 in three month long 25°C and 40°C formulation stability studies. These results open doors to an exciting realm of structure-based biologic drug design where developability and biological activity can be simultaneously optimized at the molecular engineering stages.

Treatment of rats with Phenobarbital stimulates the metabolism of bromobenzene and potentiates the hepatic necrosis elicited by the hydrocarbon. In contrast, administration of SKF 525-A or of piperonyl butoxide blocks bromobenzene metabolism and prevents the damage to the liver. These results indicate that the hepatotoxic effect of bromobenzene is mediated by a metabolite.