Paola Salvatore

Experimental Phage Therapy against Staphylococcus aureus in Mice

ABSTRACT The present study describes a bacteriophage (MSa) active against Staphylococcus aureus, including methicillin-resistant staphylococcal strains. When inoculated into mice simultaneously with S. aureus A170 (108 CFU/mouse), phage (109 PFU) rescued 97% of the mice; when applied to nonlethal (5 × 106 CFU/mouse) 10-day infections, the phage also fully cleared the bacteria. The phage MSa, delivered inside macrophages by S. aureus, kills the intracellular staphylococci in vivo and in vitro. The phage can also prevent abscess formation and reduce the bacterial load and weight of abscesses. These results suggest a potential use of the phage for the control of both local and systemic human S. aureus infections.

Circadian activity rhythm abnormalities in ill and recovered bipolar I disorder patients

OBJECTIVES Most physiological indicators of bipolar disorder (BPD) reflect current acute illness, and rarely have proved to be state-independent. Activity rhythms are highly abnormal in acute phases of BPD; we compared circadian activity rhythms in BPD I patients during ill and recovered states to those of normal controls to test the hypothesis that some abnormalities may persist. METHODS We compared 36 adult DSM-IV BPD I patients during acute mania or mixed states, and during full and sustained clinical recovery, to 32 healthy controls of similar age and sex distribution, using wrist-worn, piezoelectric actigraphic monitoring for 72 h and computed cosinor analysis of circadian activity rhythms. RESULTS We verified expected major differences between manic or mixed-state BPD I patients and matched normal controls, including phase advances averaging 2.1 h in ill BPD I patients and 1.8 h in recovered patients. Moreover, recovered BPD patients differed highly significantly from controls in several measures, including acrophase advance, higher percentage of nocturnal sleep, and lower average daily activity (mesor). Actigraphic measures among recovered BPD patients were independent of ratings of mania (on the Young Mania Rating Scale), depression (on the Hamilton Depression Rating Scale), or rating-scale scored subjective distress, as well as the type and dose of concurrent psychotropic medication. CONCLUSIONS These findings suggest that abnormal activity rhythms, including sustained phase advances, may represent enduring (trait) characteristics of BPD patients even during clinical recovery. If verified, such indices may be useful in supporting diagnoses and as an objective phenotype for genetic or other biological studies.

Galectin-1 and galectin-3 expression in human bladder transitional-cell carcinomas

Galectin‐1 and galectin‐3 are galactoside‐binding proteins involved in different steps of tumor progression and potential targets for therapy. We have investigated the expression of these galectins in 38 human bladder transitional‐cell carcinomas of different histological grade and clinical stage and in 5 normal urothelium samples. Galectin‐1 mRNA levels were highly increased in most high‐grade tumors compared with normal bladder or low‐grade tumors. Western blot and immuno‐histochemical analysis of normal and neoplastic tissues revealed a higher content of galectin‐1 in tumors. Galectin‐3 mRNA levels were also increased in most tumors compared with normal urothelium, but levels were comparable among tumors of different histological grade. Int. J. Cancer (Pred. Oncol.) 84:39–43, 1999.

Galectin genes: Regulation of expression

In this review we have summarized the more recent studies on the expression of mammalian galectins. One interesting observation that can be made is that in most of microarrays and/or differential display analysis performed in recent years one or more galectins have been picked up. From a critical evaluation of the pertinent studies the main conclusion that can be drawn is that, although it is not yet clear whether the 14 galectins identified so far have functions in common, a striking common feature of all galectins is the strong modulation of their expression during development, differentiation stages and under different physiological or pathological conditions. This suggests that the expression of different galectins is finely tuned and possibly coordinated. In spite of these observations it is rather unexpected that very few studies have been performed on the molecular mechanisms governing the activity of galectin genes. Published in 2004.

Predominant recurrence polarity among 928 adult international bipolar I disorder patients

Baldessarini RJ, Undurraga J, Vázquez GH, Tondo L, Salvatore P, Ha K, Khalsa H‐MK, Lepri B, Ha TH, Chang JS, Tohen M, Vieta E. Predominant recurrence polarity among 928 adult international bipolar I disorder patients.

Manic-Depressive Illness: Evolution in Kraepelin's Textbook, 1883–1926

Background: The syndrome of manic‐depressive insanity (MDI), as conceptualized by Emil Kraepelin a century ago, with later refinements, continues to dominate research and clinical practice with mood disorder patients. Current understanding of Kraepelins views by Anglophones is heavily influenced by the late, highly developed, MDI concept represented in the 1921 partial English translation of the last complete edition of his textbook, the product of gradual development over several decades. Method: We reviewed all nine editions and revisions of Kraepelins Textbook (1883–1926) and other writings by him to document the evolution of his views of MDI, and characterized salient developments within biographical and historical contexts. Results: We found support for the traditional impression that Kraepelins clinical perception of similarities of various forms of periodic psychiatric disorders marked by fundamental dysregulation of excitation and inhibition of thought and behavior, as well as of mood—as distinct from chronic psychotic illnesses—encouraged his broad, mature concept of MDI. However, our findings indicate a complex evolution of Kraepelins MDI concept in the 1880s and 1890s, his use of more creative and less empirical clinical methods than traditionally believed, and his considerable personal uncertainty about making clear distinctions among MDI, dementia præcox, intermediate conditions, and paranoid disorders—an uncertainty that persisted to the end of his career in the 1920s. Conclusions: Kraepelin responded to a compelling international need for diagnostic order in nineteenth‐century psychiatry, and effectively promoted his diagnostic proposals with a widely used and influential textbook. Though his methods were less empirical than is usually realized, his legacy includes analysis of large clinical samples to describe psychopathology and illness‐course, along with efforts to define psychobiologically coherent and clinically differentiable entities, as steps toward defining psychiatric syndromes. Modern international “neo‐Kraepelinian” enthusiasm for descriptive, criterion‐based diagnosis should be tempered by Kraepelins own appreciation of the tentative and uncertain nature of psychiatric nosology, particularly in classifying illnesses with both affective and psychotic features.

Morbidity in 303 first‐episode bipolar I disorder patients

OBJECTIVES To test the hypotheses that: (i) depressive-dysthymic-dysphoric (D-type) morbidity is more prevalent than manic-hypomanic-psychotic (M-type) morbidity even from first episodes of bipolar I disorder (BPD-I) and despite treatment; (ii) initial presentations predict later morbidity; (iii) morbidity varies internationally; and (iv) early and later morbidity are similar. METHODS We followed SCID-based, DSM-IV BPD-I patients (n = 303) systematically and prospectively for two years to estimate the percent of weeks in specific morbid states from first lifetime major episodes. RESULTS Total morbidity accounted for 44% of the first two years, and D-type exceeded M-type illnesses by 2.1-fold (30%/14%) among morbidities ranking: mixed states (major + minor) >or= dysthymia >or= mania >or= major depression > hypomania > psychosis. In 164 cases, morbidities at 0.5-2.5 and 2.5-4.5 years were very similar. Depressive or mixed initial episodes predicted a 3.6-fold excess of D-type morbidity, and initial M-type episodes predicted a 7.1-fold excess of M-type morbidity over two years. Morbidity in European (EU) sites was nearly half that in the U.S., and 22% greater overall among men than women. In five comparable studies, illness accounted for 54% of follow-up time, and the ratio of D/M morbidity averaged 3.0. CONCLUSIONS In accord with four midcourse studies, morbidity from BPD-I onset, despite treatment by community standards, averaged 44%, was 68% D-type morbidity, and was strongly predicted by first-episode polarity. Lower morbidity in EU than U.S. sites may reflect differences in healthcare or social systems.

Age at onset versus family history and clinical outcomes in 1,665 international bipolar-I disorder patients

Early onset in bipolar disorder (BPD) has been associated with greater familial risk and unfavorable clinical outcomes. We pooled data from seven international centers to analyze the relationships of family history and symptomatic as well as functional measures of adult morbidity to onset age, or onset in childhood (age <12), adolescence (12-18), or adulthood (19-55 years). In 1,665 adult, DSM-IV BPD-I patients, onset was 5% in childhood, 28% in adolescence, and 53% at peak ages 15-25. Adolescent and adult onset did not differ by symptomatic morbidity (episodes/year, percentage of months ill, co-morbidity, hospitalization, suicide attempts) or family history. Indications of favorable adult functional outcomes (employment, living independently, marriage and children, and a composite measure including education) ranked, by onset: adult > adolescent > child. Onset in childhood versus adolescence had more episodes/year and more psychiatric co-morbidity. Family history was most prevalent with childhood onset, similar over onset ages 12-40 years, and fell sharply thereafter. Multivariate modeling sustained the impression that family history and poor functional, but not symptomatic, outcomes were associated with younger, especially childhood onset. Early onset was more related to poor functional outcomes than greater symptomatic morbidity, with least favorable outcomes and greater family history with childhood onset.

McLean-Harvard International First-Episode Project: Two-Year Stability of ICD-10 Diagnoses in 500 First-Episode Psychotic Disorder Patients

OBJECTIVE Because clinical and biologic research and optimal clinical practice require stability of diagnoses over time, we determined stability of ICD-10 psychotic disorder diagnoses and sought predictors of diagnostic instability. METHOD Patients from the McLean-Harvard International First-Episode Project, conducted from 1989 to 2003, who were hospitalized for first psychotic illnesses (N = 500) were diagnosed by ICD-10 criteria at baseline and 24 months, on the basis of extensive prospective assessments, to evaluate the longitudinal stability of specific categorical diagnoses and predictors of diagnostic change. RESULTS Diagnostic stability averaged 90.4%, ranking as follows: schizoaffective disorder (100.0%) > mania with psychosis (99.0%) > mixed affective episode (94.9%) > schizophrenia (94.6%) > delusional disorder (88.2%) > severe depressive episode with psychotic symptoms (85.2%) > acute psychosis with/without schizophrenia symptoms = unspecified psychosis (all 66.7%) >> acute schizophrenia-like psychosis (28.6%). Diagnoses changed by 24 months of follow-up to schizoaffective disorder (37.5%), bipolar disorder (25.0%), schizophrenia (16.7%), or unspecified nonorganic psychosis (8.3%), mainly through emerging affective features. By logistic regression, diagnostic change was associated with Schneiderian first-rank psychotic symptoms at intake > lack of premorbid substance use. CONCLUSIONS We found some psychotic disorder diagnoses to be more stable by ICD-10 than DSM-IV criteria in the same patients, with implications for revisions of both diagnostic systems.

Onset-age of bipolar disorders at six international sites.

BACKGROUND Onset-age is a stable characteristic of bipolar disorder (BPD) patients of clinical and probable psychobiological importance, but large pooled clinical samples from multiple sites employing modern diagnostic criteria to quantify onset-age remain rare. METHODS We pooled diagnostic, demographic, and clinical data from 1566 BPD patients from six international sites (5 European, 1 US) to compare onset-ages in subgroups. RESULTS Median+/-IQR onset in 1090 BP-I patients was 5.8 years younger than 476 BP-II cases (24.3+/-18.3 vs. 30.1+/-13.8 years; p<0.0001). Onset-age ranked: [a] BP-I men (23.0+/-12.8); [b] BP-I women (26.0+/-14.2); [c] BP-II men (29.7+/-19.1); and [d] BP-II women (30.1+/-17.5 years. Juvenile-onset (<or=age 20) was more common in Europe than the US (27% vs. 16%), as was childhood-onset (<13 years: 3.3% vs. 0%; both p<0.001). Proportion of all cases, and median onset for first episodes ranked: [a] BP-I psychotic (6.3%; 22.7+/-9.2); [b] BP-I manic (29.3%; 24.0+/-12.1); [c] BP-I depressed (25.1%; 24.5+/-14.9); [d] BP-I mixed (9.7%; 27.9+/-16.0); [e] BP-II depressed (26.9%; 30.0+/-19.5); and [f] BP-II hypomanic (2.8%; 33.6+/-15.1 years; p<0.0001). Among BP-I patients, onset was similar for various forms of mania and major depression; in BP-II patients initial depression was 9.6-times more frequent and diagnosed earlier than hypomania. LIMITATIONS There was some variance among sites and only 34.1% of patients were evaluated at onset. CONCLUSIONS Type I BPD began much earlier than type II; its mainly psychotic presentations occurred earliest, but BP-I men were younger than women, especially at psychotic or mixed onsets.