Similar HbA1c reduction and hypoglycaemia with variable- vs fixed-time dosing of basal insulin peglispro in type 1 diabetes: IMAGINE 7 study.

AIMS: To compare 24-hour fixed-time basal insulin peglispro (BIL) dosing with 8- to 40-hour variable-time BIL dosing for glycaemic control and safety in patients with type 1 diabetes. Primary outcome was non-inferiority of BIL variable-time dosing compared with fixed-time dosing for glycated haemoglobin (HbA1c) change after 12-week treatment (margin = 0.4%). MATERIALS AND METHODS: This Phase 3, open-label, randomized, cross-over study (N = 212) was conducted at 20 centres in the United States. During the 12-week lead-in phase, patients received BIL daily at fixed-times. Two 12-week randomized cross-over treatment phases followed, where patients received BIL dosed at either fixed- or variable-times. During the 4-week safety follow-up, patients received conventional insulins. RESULTS: During the lead-in period, least-squares mean HbA1c decreased from 7.5% to 6.8%. For BIL, variable-time dosing was non-inferior to fixed-time dosing for HbA1c change [least-squares mean difference = 0.06%, 95% confidence interval (-0.01, 0.13)]. In both regimens, HbA1c increased slightly during the cross-over periods, but remained significantly below baseline. Variable- and fixed-time dosing regimens had similar rates of total hypoglycaemia (10.4 ± 0.62 and 10.5 ± 0.67 events/patient/30 days, P = .947) and nocturnal hypoglycaemia (1.3 ± 0.11 and 1.5 ± 0.13 events/patient/30days, P = .060). Comparable proportions of patients achieved HbA1c < 7.0% with variable- [91 (54.5%)] and fixed-time dosing [101 (60.5%)]. CONCLUSIONS: Treatment with BIL allows patients to use flexible dosing intervals from 8 to 40 hours. Glycaemic efficacy (HbA1c), glycaemic variability and hypoglycaemia are similar to fixed-time dosing, suggesting that BIL could potentially provide flexibility in dosing for patients who miss their daily basal insulin.

Basal insulin peglispro versus insulin glargine in insulin-naïve type 2 diabetes: IMAGINE 2 randomized trial.

AIMS: To compare, in a double-blind, randomized, multi-national study, 52- or 78-week treatment with basal insulin peglispro or insulin glargine, added to pre-study oral antihyperglycaemic medications, in insulin-naïve adults with type 2 diabetes. MATERIAL AND METHODS: The primary outcome was non-inferiority of peglispro to glargine with regard to glycated haemoglobin (HbA1c) reduction (margin = 0.4%). Six gated secondary objectives with statistical multiplicity adjustments focused on other measures of glycaemic control and safety. Liver fat content was measured using MRI, in a subset of patients. RESULTS: Peglispro was non-inferior to glargine in HbA1c reduction [least-squares (LS) mean difference: -0.29%, 95% confidence interval (CI) -0.40, -0.19], and had a lower nocturnal hypoglycaemia rate [relative rate 0.74 (95% CI 0.60, 0.91); p = .005), more patients achieving HbA1c <7.0% without nocturnal hypoglycaemia [odds ratio (OR) 2.15 (95% CI 1.60, 2.89); p < .001], greater HbA1c reduction (p < .001), and more patients achieving HbA1c<7.0% [OR 1.97 (95% CI 1.57, 2.47); p < .001]. Total hypoglycaemia rate and fasting serum glucose did not achieve statistical superiority. At 52 weeks, peglispro-treated patients had higher triglyceride (1.9 vs 1.7 mmol/L). alanine transaminase (34 vs 27 IU/L), and aspartate transaminase levels (27 vs 24 IU/L). LS mean liver fat content was unchanged with peglispro at 52 weeks but decreased 3.1% with glargine [difference: 2.6% (0.9, 4.2); p = .002]. More peglispro-treated patients experienced adverse injection site reactions (3.5% vs 0.6%, p < .001). CONCLUSIONS: Compared with glargine at 52 weeks, peglispro resulted in a statistically superior reduction in HbA1c, more patients achieving HbA1c targets, less nocturnal hypoglycaemia, no improvement in total hypoglycaemia, higher triglyceride levels, higher aminotransferase levels, and more injection site reactions.

Comparison of insulin lispro protamine suspension versus insulin glargine once daily added to oral antihyperglycaemic medications and exenatide in type 2 diabetes: a prospective randomized open-label trial.

AIMS: To compare efficacy and safety of two, once-daily basal insulin formulations [insulin lispro protamine suspension (ILPS) vs. insulin glargine (glargine)] added to oral antihyperglycaemic medications (OAMs) and exenatide BID in suboptimally controlled type 2 diabetes (T2D) patients. METHODS: This 24-week, open-label, multicentre trial randomized patients to bedtime ILPS (n = 171) or glargine (n = 168). Non-inferiority of ILPS versus glargine was assessed by comparing the upper limit of 95% confidence intervals (CIs) for change in haemoglobin A1c (HbA1c) from baseline to week 24 (adjusted for baseline HbA1c) with non-inferiority margin 0.4%. RESULTS: Non-inferiority of ILPS versus glargine was demonstrated: least-squares mean between-treatment difference (ILPS minus glargine) (95% CI) was 0.22% (0.06, 0.38). Mean HbA1c reduction was less for ILPS- versus glargine-treated patients (-1.16 ± 0.84 vs. -1.40 ± 0.97%, p = 0.008). Endpoint HbA1c < 7.0% was achieved by 53.7% (ILPS) and 61.7% (glargine) (p = NS). Overall hypoglycaemia rates (p = NS) and severe hypoglycaemia incidence (p = NS) were similar. Nocturnal hypoglycaemia rate was higher in patients treated with ILPS versus glargine (p = 0.004). Weight gain was similar between groups (ILPS: 0.27 ± 3.38 kg; glargine: 0.66 ± 3.93 kg, p = NS). Endpoint total insulin doses were lower in patients treated with ILPS versus glargine (0.30 ± 0.17 vs. 0.37 ± 0.17 IU/kg/day, p < 0.001). CONCLUSIONS: ILPS was non-inferior to glargine for HbA1c change over 24 weeks, but was associated with less HbA1c reduction and more nocturnal hypoglycaemia. Treat-to-target basal insulin therapy improves glycaemic control and is associated with minimal weight gain when added to OAMs and exenatide BID for suboptimally controlled T2D.

Very late activation antigens on rheumatoid synovial fluid T lymphocytes. Association with stages of T cell activation.

Lymphocytes from the synovial fluid of eight out of eight rheumatoid arthritis (RA) patients had elevated very late activation antigen-1 (VLA-1) expression (10-36% positive cells), whereas peripheral blood lymphocytes (PBL) from RA patients and healthy controls had low VLA-1 expression (0-6% positive cells). During 1-2 wk of in vitro culture, VLA-1 increased on synovial fluid cells but remained low on PBL. In comparison, the interleukin 2 receptor (IL-2 R) was less prominent than VLA-1 on fresh synovial fluid cells, did not increase on cultured synovial fluid T cells, but did increase greatly on cultured PBL. The mitogen PHA reversed or prevented the appearance of VLA-1+, IL-2 R- synovial fluid cells during in vitro culture, thus giving IL-2 R+, VLA-1- cells. These results emphasize that VLA-1+ SF cells are different from resting cells or IL-2 R+ activated PBL T cells, and VLA-1 on synovial fluid T cells may be incompatible with mitogen stimulation. In addition, the VLA-2 heterodimer (165,000/130,000 relative molecular mass [Mr]) was regulated opposite to the VLA-1 heterodimer (130,000/210,000 Mr) on synovial lymphocytes, and thus the VLA-1/VLA-2 ratio is another indicator of the stage of T cell activation.

Mustard operation in the 1st month of life.

Since April 1976, nine infants less than 1 month of age underwent a Mustard intraatrial baffle procedure. All had transposition of the great arteries and were persistently symptomatic or hypoxic after the Rashkind balloon atrioseptostomy. Two had an associated large ventricular septal defect patched at the time of physiologic correction. The average age of the infants was 11.6 days (range 36 hours to 28 days). Weight averaged 3.4 kg (range 2.5 to 4.2). In all the Mustard procedure was performed using deep hypothermic circulatory arrest, averaging 71 minutes (range 48 to 88) at a mean core temperature of 13 degrees C. An average of 2.8 days of postoperative ventilatory assistance was required. One death occurred in a 28 day old male infant with an associated ventricular septal defect who, the morning after operation, had a sudden unresponsive cardiac standstill. The postoperative hospitalization period averaged 15 days (range 10 to 23). Follow-up evaluation has extended from 4 to 63 months (average 31). Six patients were restudied 2 to 21 months postoperatively. One had obstruction of the superior limb of the baffle, which had separated from the right atrial wall permitting a modest right to left shunt. She has had uneventful repair employing a unique modification of Senning's operation. Another child has asymptomatic partial obstruction of the superior limb of the baffle demonstrated angiographically. None has pulmonary venous obstruction and all have prevailing normal sinus rhythm. Significant right ventricular dysfunction has been demonstrated in one. Early correction in these persistently symptomatic or hypoxic neonates with transposition of the great arteries with or without a ventricular septal defect has obviated the need for palliative operations and produced gratifying early and late results.

Biologic reconstruction of the right ventricular outflow tract. Preliminary experimental analysis and clinical application in a neonate with type I truncus arteriosus.

A unique concept of right ventricular outflow tract reconstruction is presented. Applications of this concept, employing a glutaraldehyde-preserved heterograft mitral valve leaflet mounted directly to the right ventricle, was studied in six immature goat models. Interval evaluation of these models demonstrated no significant outflow tract obstruction or aneurysm. Only one animal had significant pulmonary outflow regurgitation angiographically at the time of sacrifice. All heterograft valve leaflets showed a degree of calcification and/or retraction directly related to the time interval between implant and sacrifice. Encouraging early results were obtained with this method of pulmonary outflow tract reconstruction in a 2,400 gram neonate with type I truncus arteriosus.

Anatomic correction of interrupted aortic arch complex in neonates.

Anatomic correction of interrupted aortic arch complex by direct aortic anastomosis was accomplished in five neonates ranging in age from 2 to 19 days. Three had type B and two had type A interruption of the aortic arch. All operations were performed through a transverse bilateral thoracotomy by use of hypothermic circulatory arrest. The descending thoracic aorta is widely mobilized to the level of the diaphragm. The ductus arteriosus is completely excised and the descending aortic segment is anastomosed end to side to the ascending aorta. The large ventricular septal defect is patched with Dacron velour, and atrial communications are closed with running suture. Three of the babies survived surgery and are making satisfactory clinical progress. All three have been restudied on a routine basis. They were found to have excellent anatomic repairs with no residual intracardiac shunts. There was a peak systolic gradient of 8 mm Hg at the aortic anastomosis in the second survivor; however, she does not have ascending aortic hypertension. The first and last survivors have no aortic gradients. It is recommended that a newborn with interrupted aortic arch complex be subjected to corrective surgery as the procedure of choice. Excellent results may be expected when surgery is done prior to irreversible metabolic decompensation of the patient.

Thoracic aortic injury. A ten-year experience.

Between 1974 and 1983, 41 patients arrived alive at Loma Linda (Calif) University Medical Center after sustaining a traumatic disruption of the thoracic aorta. Four patients died during the resuscitation attempts and the 37 patients who survived underwent thoracotomy for attempted definitive repair. There were six hospital deaths (16.22%) among those who underwent definitive repair; associated injuries (mostly orthopedic and neurologic) were contributing factors. Four patients were discharged with spinal cord injuries, two were paraplegic on arrival at the hospital, and two became paraplegic postoperatively (surgical spinal cord injury, 5.41%). Most injuries were distal to the left subclavian artery (97.56%). Cardiopulmonary (left heart) bypass was gradually abandoned in favor of more simple techniques, including ventriculoaortic and aorto-aortic heparinized shunts or a "clamp and sew" method. Experience has demonstrated that most traumatic aortic disruptions can be repaired safely by direct suture technique (without graft interposition) if accomplished during the acute episode.

Repair of interrupted aortic arch and aortopulmonary window in an infant.

The diagnosis and repair in infancy of interrupted aortic arch and aortopulmonary window is described. Using deep hypothermia and circulatory arrest, aortic continuity was established with a prosthetic graft, which was anastomosed to the aortic orifice of the aortopulmonary window. The pulmonary artery side of the aortopulmonary window was closed directly. Postoperative cardiac catheterization demonstrated a good reconstruction. Previous experience with this rare variety of interrupted aortic arch complex is reviewed.

Interrupted aortic arch complex: successful total correction in the neonate.

Two neonates subjected to definitive repair of interrupted aortic arch complex during the first week of life are presented. Results correlated well with preoperative status. Our definition of complete correction, including direct aortic anastomosis, is discussed along with the surgical strategy employed for successful repair of this otherwise dismal anomaly.

Impalement injuries to the thorax as a result of motor vehicle accidents.

We report three cases of thoracic impalement by large-diameter steel pipes as a result of motor vehicle accidents. The steel pipes were removed in all patients in the operating room under general anesthesia and controlled circumstances. Despite the dramatic nature and presentation of these injuries, all 3 patients had nonlethal injuries and have recuperated without sequelae. Orderly care with standard surgical procedures is required and will give good results.

Fluoxetine treatment for obsessive-compulsive disorder in children and adolescents: a placebo-controlled clinical trial.

OBJECTIVE: This study assesses the efficacy and tolerability of fluoxetine in the acute treatment of child and adolescent obsessive-compulsive disorder (OCD) during a 13-week, double-blind, placebo-controlled study. METHOD: Eligible patients aged 7 to 17 (N = 103) were randomized at a ratio of 2:1 to receive either fluoxetine or placebo. Dosing was initiated at 10 mg daily for 2 weeks, then increased to 20 mg daily. After 4 weeks of treatment, and again after 7 weeks of treatment, non-responders could have their dosage increased by 20 mg daily, for a maximum possible dosage of 60 mg daily. Primary measure of efficacy was improvement in OCD symptoms as measured by the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS). All analyses were intent-to-treat. RESULTS: Fluoxetine was associated with significantly greater improvement in OCD as assessed by the CY-BOCS (p = .026) and other measures than was placebo. Fluoxetine was well tolerated and had a rate of discontinuation for adverse events similar to that of placebo (p = 1.00). CONCLUSIONS: Fluoxetine 20 to 60 mg daily was effective and well tolerated for treatment of OCD in this pediatric population.

Discontinuation symptoms: comparison of brief interruption in fluoxetine and paroxetine treatment.

Abrupt interruption or cessation of selective serotonin reuptake inhibitor (SSRI) treatment may result in discontinuation or treatment interruption symptoms. Recent reports suggested these symptoms occur more frequently with shorter half-life SSRIs. Previous studies indicated a 5-8-day treatment interruption resulted in fewer discontinuation-emergent adverse events in fluoxetine-treated patients than in paroxetine-treated patients. This study examines the effects of shorter treatment interruption (3-5 days), as would occur if patients miss just a few doses of medication. Patients successfully treated for depression with fluoxetine or paroxetine underwent treatment interruption in a double-blind fashion. Treatment interruption-emergent symptoms were assessed using the Discontinuation-Emergent Signs and Symptoms checklist. Other assessments included the Montgomery-Asberg Depression Rating Scale, Clinical Global Impressions-Severity scale and a social functioning questionnaire. Of 150 patients enrolled, 141 completed the study. Following treatment interruption, fluoxetine-treated patients experienced fewer treatment interruption-emergent events than did paroxetine-treated patients. The paroxetine treatment group also experienced significant increases in depressive symptoms, clinical global severity scores and difficulty in social functioning; the fluoxetine treatment group did not. These results are consistent with reports suggesting abrupt interruption of treatment with paroxetine is more often associated with somatic and psychological symptoms than is abrupt interruption of fluoxetine. Patients treated with fluoxetine appeared to be protected by its longer half-life.

Signal affects and our psychoanalytic confusion of tongues.

Difficulties psychoanalysts of different points of view have in communicating with one another are reviewed. Reexamination of the structural theory distinguishes the tripartite theory of 1923 from the signal affect model of 1926; the latter concept is traced through the post-Freudian relational points of view. This signal affect model provides a base for what the author sees as a core commonality among the diverse current theories, as well as a basis for sharper, more empirically arguable differentiation of the divergences and incompatibilities among them. The interest in and acceptance, in recent years, of Ferenczi's contributions in his 1933 paper on confusion of tongues reflect a shift in our views of psychoanalytic technique over the intervening years, toward an interactional view of the psychoanalytic process. The relational points of view have been instrumental in this shift, by direct contributions, and indirectly by challenging and inspiring the classical viewpoint to develop and change. The relational points of view, in addition to focusing on different contents, also prescribe differences in technical approach and in the climate within which an analysis is conducted, presenting valuable alternatives in clinical work. Finally, arguments are offered in favor of clinicians using multiple theoretical points of view for access to the varied clinical tasks demanded by analytic work.

Developmental observation, multiple models of the mind, and the therapeutic relationship in psychoanalysis.

This overview of the therapeutic relationship in psychoanalysis utilizes a sampling of findings of infant observational research to illuminate issues in the evolving technique of psychoanalysis. The therapeutic relationship is followed schematically through the course of a treatment, from initial contact through termination, and the gradual shift of psychoanalytic technique toward an interactional view of the psychoanalytic situation is noted. During the middle phase, some areas of current controversy in psychoanalysis are discussed, along with views on the multiple theoretical models currently available for organizing psychoanalytic data and for gaining clinical access for analytic work.

The structural theory and the representational world.

I have attempted to articulate a means of incorporating representational world concepts firmly within the structural theory, while still maintaining their clarity, a view which I believe can be useful both clinically and theoretically. It can facilitate an analyst's working with complex clinical material that reflects conflicts at multiple developmental levels, without forcing a premature commitment to restrictive conceptualizations which could impede his listening to the full richness of the material. In addition, I have argued that the perpetual resurgences of representational world psychologies may be understood as an indication of the need for the inclusion of those phenomena in our theory in a clear and integrated way. Finally, I have presented some basis for suggesting that the drive-defense and the representational world models represent coordinate aspects of the structural theory, each with its vantage points for highlighting and clarifying certain phenomena, but best used complementarily in our observations of psychopathology at all levels of development. I do not believe this represents a totally new view or departure within psychoanalytic thinking. On the contrary, I have assembled, organized, and attempted to make explicit certain understandings which I believe we often apply naturally through the use of empathy and intuitive gifts. In an analysis which is going well, an analyst operating within a drive-defense framework is almost certainly finding some natural way of dealing with self and object issues, even if he does not formulate them explicitly to himself. To set down and make explicit, however, the functions we may much of the time perform without awareness is worthwhile preparation against times of difficulty in understanding a particular case. At those times we need at our disposal as specific, as inclusive, and as illuminating a theory as we can find to assist us. It is that clinical need which has guided me in these attempts at theoretical clarification.

The structural theory and the representational world: developmental and biological considerations.

Although the intriguing question of whether the division into two viewpoints within the structural theory is a theoretical convenience or whether it mirrors fundamental psychobiological truths is not capable of full resolution at the moment, fortunately that resolution is not required for our usual clinical purposes. I believe that analytic work presents us with data readily conceptualized now from one, now from the other, viewpoint, so that analytic understanding benefits from the analyst's shifting his frame of reference from moment to moment in listening and associating to the patient's material. I believe that in every event within the analytic situation or in a person's life, our understanding is deepened and made more complete by approaching the phenomena from both vantage points, bearing in mind that the same ego we conceptualize as testing, assessing, and evaluating emergent drives is also assessing the congruence or discrepancy between the wished-for and perceived states of the representational world. These processes are occurring both in the analysand and in the analyst who is attempting to resonate with and understand the intrapsychic functioning of his patient. They constitute two observational vantage points within the structural theory, organizations of motives (Friedman, 1980) either of which may offer the most immediate access to understanding a particular segment of clinical material. I believe our understanding is most often deepened, however, by subsequent scrutiny in the light of the other model. I have tried here to supplement my previous exposition of a representational world point of view (J.G. Jacobson, 1983) by providing some of its developmental, ethological, and psychophysiological landmarks and underpinnings.

Cell matrix adhesion-related proteins VLA-1 and VLA-2: regulation of expression on T cells.

The mitogens phytohemagglutinin (PHA) and concanavalin A inhibited the appearance of the very late activation antigen (VLA)-1, but did not inhibit VLA-2 expression on cultured activated T cells. In contrast to diminished VLA-1 expression, mitogen treatment caused increased cell surface expression of other activation antigens such as T10, HLA-DR, interleukin 2 (IL 2) receptor, and 4F2, and greater cell proliferation. Conversely, when T cells were not repetitively restimulated with mitogen, these less proliferative "postactivated" T cells had elevated VLA-1 expression. The diminished expression of VLA-1 caused by PHA was reversible since subsequent removal of mitogen was associated with increased VLA-1, paralleled by a decrease in interleukin 2 receptor levels. In addition to preventing or delaying the initial appearance of VLA-1, PHA stimulation also was somewhat effective in causing the disappearance of VLA-1 already present, especially on recently established cultures. However, cultures that had either never seen PHA, not seen PHA for several weeks, or been stimulated regularly with PHA, but were several months old, did not lose VLA-1 in response to PHA stimulation, suggesting that a state of insensitivity to PHA effects could be attained. Unlike PHA-stimulated T cells, T cells repetitively restimulated with alloantigen or the monoclonal antibody T3 did not show a marked absence of VLA-1 but rather showed an increased level of VLA-2 relative to VLA-1. Taken together, results of stimulation by either mitogen, alloantigen, or anti-T3 monoclonal antibody support the conclusion that T cell stimulation in general can cause a decreased VLA-1:VLA-2 ratio, whether by decreased VLA-1 or increased VLA-2. These shifts in VLA-1:VLA-2 ratios are probably not simply the result of shifts in the relative proportions of different subpopulations, because similar growth-related changes in this ratio were observed on the T cell line ANITA, which is a homogeneous population of cells. Because both VLA-1 and VLA-2 are differentially regulated on cultured, long term activated T cells depending on stage of activation and growth conditions, and are members of a family of at least five heterodimers that includes cell matrix adhesion molecules, we suggest that these studies will provide clues to novel aspects of T cell growth regulation, perhaps relating to T cell-matrix adhesion.

A conserved open reading frame that overlaps the herpes simplex virus thymidine kinase gene is important for viral growth in cell culture.

Of 18 mutants containing clustered point mutations within UL24 (an open reading frame that overlaps the herpes simplex virus thymidine kinase gene on the opposite strand), 15 formed small plaques and were substantially impaired for virus growth in cell culture. Mutations conferring the small plaque phenotype disrupt regions of UL24 that share considerable sequence similarity with open reading frames common to herpesviruses of mammals and birds. We infer that UL24 is expressed and important for virus growth in cell culture and suggest that possible effects on UL24 should be considered in studies of thymidine kinase-deficient mutants.