Nanomedicines: From Bench to Bedside and Beyond

Advancing nanomedicines from concept to clinic requires integration of new science with traditional pharmaceutical development. The medical and commercial success of nanomedicines is greatly facilitated when those charged with developing nanomedicines are cognizant of the unique opportunities and technical challenges that these products present. These individuals must also be knowledgeable about the processes of clinical and product development, including regulatory considerations, to maximize the odds for successful product registration. This article outlines these topics with a goal to accelerate the combination of academic innovation with collaborative industrial scientists who understand pharmaceutical development and regulatory approval requirements—only together can they realize the full potential of nanomedicines for patients.     

Acute myeloid leukemia: current progress and future directions

Progress in the understanding of the biology and therapy of acute myeloid leukemia (AML) is occurring rapidly. Since 2017, nine agents have been approved for various indications in AML. These included several targeted therapies like venetoclax, FLT3 inhibitors, IDH inhibitors, and others. The management of AML is complicated, highlighting the need for expertise in order to deliver optimal therapy and achieve optimal outcomes. The multiple subentities in AML require very different therapies. In this review, we summarize the important pathophysiologies driving AML, review current therapies in standard practice, and address present and future research directions.Subject terms: Prognosis, Health services     

The clinical phenotypes of juvenile bipolar disorder: toward a validation of the episodic-chronic-distinction.

BACKGROUND: Recent research has addressed the issue of subtyping juvenile bipolar disorder (JBD). Accordingly, we set out to find out, in a naturalistic sample of bipolar children and adolescents with mania and mixed mania, whether the most useful subtyping should be based on clinical features (elated vs. irritable) or course (episodic vs. chronic). METHODS: We studied 136 patients, 81 male patients (59.6%) and 55 female patients (40.4%), mean age 13.5 +/- 2.9 years, meeting the DSM-IV diagnosis of bipolar disorder, assessed by a structured clinical interview (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version [K-SADS-PL]). RESULTS: Regarding course, 77 patients (56.6%) had an episodic course and 59 patients (43.4%) had a chronic course. Patients with chronic course were significantly younger, had an earlier onset of JBD, and presented a more frequent comorbidity with disruptive behavior disorders. According to the prevalent mood disturbance, 75 patients (55.1%) showed an elated and 61 patients (44.9%) showed an irritable mood. Elated mood was more frequent in patients with episodic course, whereas irritable mood was more frequent in the patients with chronic course. CONCLUSIONS: These findings suggest that chronic versus episodic course may be a putative differential feature. Further validation of such a distinction would require prospective studies, temperament evaluation, gender and neurobiologic approaches, and differential psychopharmacologic assignment and response.     

Immune cell imbalance in major depressive and panic disorders.

We investigated subsets of peripheral immunologic cells in 12 drug-free patients affected by major depression according to DSM-III-R criteria, and who had recent evidence of somatic diseases. They were compared with 10 drug-free depressives, with 10 patients with panic disorder, and with 12 healthy volunteers, all without somatic disease. The immune subsets were measured by flow cytometry. The results showed that both groups of depressives had the same abnormalities in immune cells compared with the healthy volunteers or the panic disorder patients; in particular they presented a lower number of CD3+, CD8+ and HLA-DR+. The patients with panic attacks did not differ from healthy controls, except for CD4+ cells which were significantly lowered, even in comparison with the depressive groups. These data, although preliminary and in a small sample, suggest that some immune parameters may be influenced by the presence of a major psychiatric disorder.     

The clinical spectrum of so-called "minor" depressions.

Reviewing the recent literature on the overlapping spectrum of neurotic depressive and dysthymic conditions--unofficially referred to as "minor," "atypical" or "characterologic" depressives--the authors conclude that significant symptomatologic admixtures with anxiety disorders do not represent the prototypical features of these disorders as defined in DSM-III-R. It is long-standing anhedonia on an intermittent or chronic basis which appears to characterize the trait illness of dysthymia. The emerging data on dysthymia suggest that it begins early in life, is often complicated by major depressions, and pursues a chronic--often pernicious--course. The development of hypomanic switches during the prospective course of some of these patients further suggests some kinship to bipolar disorder. Although traditionally conceived as being largely "psychogenic," familial data and selected biologic indices--especially in the area of sleep--and thymoleptic responsiveness impart some credibility to the role of biologic factors in the origin of these disorders. Given the high prevalence of dysthymic conditions in clinical practice, new research strategies on their causes are needed as a precondition for more rational treatment approaches.     

The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis of the ECA database taking into account subthreshold cases

BACKGROUND: Despite emerging international consensus on the high prevalence of the bipolar spectrum in both clinical and community samples, many skeptics contend that narrowly defined bipolar disorder with a lifetime rate of about 1% represents a more accurate estimate of prevalence. This may in part be due to the fact that higher figures proposed for the bipolar spectrum (5-8%) have not been based on national data and have not included all levels of manic symptom severity. In the present secondary analyses of the US National Epidemiological Catchment Area (ECA) database, we provide further clarification on this fundamental public health issue. METHODS: All respondents in the first wave (first interview) of the ECA household five site sample (n=18252) were classified on the basis of DSM-III criteria into lifetime manic and hypomanic episodes, as well as those with at least two lifetime manic/hypomanic symptoms below the threshold for at least 1 week duration (subsyndromal manic symptoms [SSM] group). Odds ratios were calculated on lifetime service utilization for mental health problems, measures of adverse psychosocial outcome, and suicidal behavior compared to subjects with no mental disorders or manic symptoms. RESULTS: As originally reported nearly two decades ago by the primary investigators of the ECA, the lifetime prevalence for manic episode was 0.8%, and for hypomania, 0.5%. What is new here is the inclusion of subthreshold SSM subjects, which accounted for 5.1%, yielding a total of 6.4% lifetime prevalence for the bipolar spectrum. All three (manic, hypomanic and SSM) groups had greater marital disruption. There were significant increases in lifetime health service utilization, need for welfare and disability benefits and suicidal behavior when the SSM, hypomanic and manic subjects were compared to the no mental disorder group. Suicidal behavior was non-significantly highest in the hypomanic (bipolar II) group. Otherwise, hypomanic and manic groups had comparable level of service utilization and social disruption. LIMITATIONS: Comorbid disorders, which might influence functioning, were not included in the present analyses. CONCLUSION: These secondary analyses of the US National ECA database provide convincing evidence for the high prevalence of a spectrum of bipolarity in the community at 6.4%, and indicate that subthreshold cases are at least five times more prevalent than DSM-based core syndromal diagnoses at about 1%. These SSM subjects, who met the criteria of "caseness" from the point of view of harmful dysfunction, are of great theoretical and public health significance.     

Affective temperaments in clinically-well subjects in Turkey: initial psychometric data on the TEMPS-A

BACKGROUND: This is a first attempt to evaluate the reliability and factor structure replicability of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Autoquestionnaire (TEMPS-A) in its Turkish Version. The questionnaire is a self-report 110-item measure that postulates five affective temperaments-the depressive, cyclothymic, irritable, hyperthymic, and anxious-which embody both strengths and liabilities along affective lines. METHODS: The questionnaire was administered to 658 clinically-well subjects in a Turkish university circle. We undertook item analysis and test-retest reliability. We then examined internal consistency through factor analysis with PCA rotation. RESULTS: We found good to excellent test-retest reliability (0.73-0.91), and internal consistency (0.77-0.85). We deleted 10 items with factor loading <0.20 for their own subscales, resulting in a questionnaire with 99 items. Despite considerable overlap between depressive and cognitive anxiety traits, a distinct "nervous"-anxious factor emerged as well, and the hypothesized (original English) 5-factor structure of the TEMPS-A was supported. Cut-offs for each temperament were based on z-scores higher than +2S.D. Dominant irritable (3.7%), nervous-anxious (3.7%) and depressive (3.1%) temperaments were the most common in this population, whereas dominant cyclothymic (1.7%) and hyperthymic (1.2%) temperaments were relatively uncommon. These temperaments tended to lose their intensity with age. As expected, women scored significantly higher on the nervous-anxious, and men on the hyperthymic temperaments. LIMITATIONS: The sample was composed of younger subjects with higher education than the general population of Turkey. Although the distribution of the scores for each of the temperaments deviated somewhat from normal curves, for heuristic reasons we did attempt to provide prevalence rates based on z-scores. CONCLUSION: In this preliminary version of the TEMPS-A, we have retained 100 (of the original 110) traits loading >0.20. Some deleted items referred to sleep, others appeared socially desirability traits in the Turkish culture endorsed by many subjects. Nonetheless, item analyses within each factor revealed traits indicative of personal assets (specific to each temperament) along with those which might represent vulnerability to affective illness. This is in line with the hypothesized original theoretical framework of the senior authors. Even in this "first pass," in its Turkish version the TEMPS-A is a reliable and valid instrument. Further refinement of the instrument will require the study of a nationally representative sample in Turkey.     

Clinical characterization of depressive mixed state in bipolar-I patients: Pisa-San Diego collaboration

BACKGROUND: Although mixed states were classically described as various concomitant admixtures of depression and mania, the official current definitions in both DSM-IV and ICD-10 tend to restrict the concept to manic patients with full syndromal depression. Recent research has actually shown that mania with few depressive symptoms constitutes the most prevalent clinical presentation of mixed or dysphoric mania. Major depressive patients with few concomitant manic symptoms are not officially recognized within the current nosology. In this paper we attempt to delineate the clinical profile of such depressive mixed states in the context of bipolar I disorder. METHODS: In the Pisa day center, we studied 195 bipolar I patients who either met Pisa criteria for bipolar mixed state (n=159) or DSM-III-R criteria for major depressive episode (bipolar major depression or B-MD, n=36). Of the 159 patients identified by Pisa criteria as mixed state, 86 also met the criteria of the DSM-III-R for mixed episode (core mixed state or MS group), while 32 met the DSM III-R criteria for major depressive episode (provisionally defined as depressive mixed states, D-MS); the remaining patients (n=41, 25.7%) with predominatly manic picture were not included in the present comparisons. RESULTS: The three groups (B-MD, MS and D-MS) had close similarities in clinical and sociodemographic characteristics such as age, sex distribution, marital status, schooling, residence, age at onset, age of first treatment, age of first hospitalization, degree of chronicity of the index episode, stressor within the 6 months before the index episode, lifetime suicide attempts and premorbid temperament. First degree family history for bipolar illness and that for other mental disorders was also similar, except for major depression that was more common among the relatives of D-MS. MS and D-MS were further distinguished from B-MD by the fact that the latter followed a more 'cyclic' course with shorter yet greater number of episodes, and which began with a pure depressive episode; by contrast, MS and D-MS had fewer episodes of longer duration, less interepisodic remission, and tended to begin with a mixed episode. Incongruous psychotic features were more common in the two mixed groups compared to B-MD, and the most common features of the D-MS group were agitation, psychotic depression with irritable mood, pressured speech and/or flight of ideas. LIMITATION: It was not feasible to collect information blind to clinical status in patients with severe psychotic mood states. CONCLUSION: These data confirm the existence of psychotic agitated depressive mixed states with flight of ideas, distinct from cyclic retarded pure bipolar depressive states. The recognition of these affective states is clinically important to protect patients from the potentially harmful indiscriminate use of antidepressants and to provide them with the benefits of an anticonvulsant, a short-term neuroleptic, or ECT.