In vivo quantitative imaging of hippocampal inflammation in autoimmune neuroinflammatory conditions: a systematic review.

The hippocampus is a morphologically complex region of the brain limbic system centrally involved in important cognitive, affective, and behavioural regulatory roles. It has exquisite vulnerability to neuroinflammatory processes, with some of its subregions found to be specific sites of neuroinflammatory pathology in ex-vivo studies. Optimizing neuroimaging correlates of hippocampal neuroinflammation would enable the direct study of functional consequences of hippocampal neuroinflammatory pathology, as well as the definition of therapeutic end-points for treatments targeting neuroinflammation, and their related affective or cognitive sequelae. However, in vivo traditional imaging of the hippocampus and its subregions is fraught with difficulties, due to methodological challenges deriving from its unique anatomical characteristics. The main objective of this review is to provide a current update on the characterization of quantitative neuroimaging correlates of hippocampal neuroinflammation by focusing on three prototypical autoimmune neuro-inflammatory conditions [multiple sclerosis (MS), systemic lupus erythematosus (SLE), and autoimmune encephalitis (AE)]. We focused on studies employing TSPO-targeting positron emission tomography (PET), quantitative magnetic resonance imaging (MRI), and spectroscopy techniques assumed to be sensitive to neuroinflammatory tissue changes. We found 18 eligible studies (14, 2, and 2 studies in MS, AE, and SLE, respectively). Across conditions, the largest effect was seen in TSPO PET and diffusion-weighted MRI studies. No study examined neuroinflammation-related changes at the hippocampal subfield level. Overall, results were largely inconsistent due to heterogeneous imaging methods, small sample sizes, and different population studies. We discuss how these data could inform future study design and conclude by suggesting further methodological directions aimed at improving the precision and sensitivity of neuroimaging techniques to characterize hippocampal neuroinflammatory pathology in the human brain.

Primary psychosis with comorbid drug abuse and drug-induced psychosis: Diagnostic and clinical evolution at follow up.

The study reports a follow-up assessment of 48 patients with concomitant drug abuse at the first admission for psychosis. We focused on the diagnostic distinction between primary psychosis with concomitant drug abuse and drug induced psychosis, to observe whether the diagnoses are stable over time and whether the clinical course significantly differs. The study examined 25 primary psychotic disorder with comorbid drug abuse and 23 drug-induced psychotic disorder patients. Diagnostic and psychopathological assessments were made at baseline and at follow-up. Mean follow-up period was 4.96 years. Patients with comorbid Drug Abuse exhibited higher scores in the item Unusual Content of Thought at baseline than drug-induced psychotic disorder patients: 5.48 vs 4.39 while the two patients groups did not differ in any of the BPRS items evaluated at follow-up. The primary psychosis with comorbid drug abuse and the substance induced psychosis groups were similar regarding diagnostic stability, and a diagnosis of schizophrenia at follow-up occurred similarly. There was no evidence that Drug Induced psychotic patients' symptoms tend to improve more after cessation of drug abuse. An earlier age of onset was found in primary psychotic patients, particularly for patients diagnosed as affected by schizophrenia at follow up. These results might reflect the uncertainty of the distinction between Primary and Drug Induced Psychosis and the difficulties in applying the DSM IV-TR criteria for diagnosing comorbid drug use disorders and psychotic disorders.

Clinical and neuropsychological correlates of major depression following post-traumatic brain injury, a prospective study.

OBJECTIVES: Major depression disorder (MDD) is the most frequent psychiatric complication after traumatic brain injury (TBI), with a prevalence of 14-77%. The aim of this study was to analyse the psychiatric sequelae of TBI, and to identify the neuropsychological and psychopathological correlates of post-TBI MDD in order to highlight their differences from those of primary MDD. METHODS: This was a longitudinal, prospective, case-control study. Sixteen patients with closed brain injury, and a lesion revealed by computed tomography (CT), were recruited and were evaluated one (T1), three (T3) and six (T6) months after discharge from Neurosurgery Department; the controls were six patients with MDD. The psychiatric symptoms were evaluated using brief psychiatric rating scale (BPRS), Hamilton depression rating scale (HRSD), Beck depression inventory scale (BDI), Hamilton anxiety rating scale (HRSA), global assessment of functioning (GAF) and instrumental activity of daily living (IADL). Neuropsychological profiles were assessed by using neuropsychological tests, focused on memory and frontal-executive functioning. RESULTS: At T1, MDD was observed in 10 cases (62.5%), a manic episode in 12.5%, and post-traumatic stress disorder in 6.5%. At T3 and T6, MDD was diagnosed in, respectively, eight (50%) and six cases (37.5%). Post TBI MDD had less severe depressive symptoms, showed greater social isolation and hostility and more cognitive deficits in comparison with the control group. CONCLUSIONS: MDD is a frequent TBI complication. Patients with post-TBI MDD have a specific psychopathological profile characterised by a less severe depressive symptomatology and a neuropsychological pattern that is significantly associated with greater deficits in cognitive functions than those with primary MDD.

Age independently affects myelin integrity as detected by magnetization transfer magnetic resonance imaging in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a heterogeneous disorder with a progressive course that is difficult to predict on a case-by-case basis. Natural history studies of MS have demonstrated that age influences clinical progression independent of disease duration. OBJECTIVE: To determine whether age would be associated with greater CNS injury as detected by magnetization transfer MRI. MATERIALS AND METHODS: Forty MS patients were recruited from out-patient clinics into two groups stratified by age but with similar clinical disease duration as well as thirteen controls age-matched to the older MS group. Images were segmented by automated programs and blinded readers into normal appearing white matter (NAWM), normal appearing gray matter (NAGM), and white matter lesions (WMLs) and gray matter lesions (GMLs) in the MS groups. WML and GML were delineated on T2-weighted 3D fluid-attenuated inversion recovery (FLAIR) and T1 weighted MRI volumes. Mean magnetization transfer ratio (MTR), region volume, as well as MTR histogram skew and kurtosis were calculated for each region. RESULTS: All MTR measures in NAGM and MTR histogram metrics in NAWM differed between MS subjects and controls, as expected and previously reported by several studies, but not between MS groups. However, MTR measures in the WML did significantly differ between the MS groups, in spite of no significant differences in lesion counts and volumes. CONCLUSIONS: Despite matching for clinical disease duration and recording no significant WML volume difference, we demonstrated strong MTR differences in WMLs between younger and older MS patients. These data suggest that aging-related processes modify the tissue response to inflammatory injury and its clinical outcome correlates in MS.

Clinical pharmacology of atypical antipsychotics: an update.

This review will concentrate on the clinical pharmacology, in particular pharmacodynamic data, related to atypical antipsychotics, clozapine, risperidone, paliperidone, olanzapine, que¬tiapine, amisulpride, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone and cariprazine. A summary of their acute pharmacokinetics properties are also reported. Four new second-generation antipsychotics are available: iloperidone, asenapine, lurasidone and in the next future cariprazine. Similar to ziprasidone and aripiprazole, these new agents are advisable for the lower propensity to give weight gain and metabolic abnormalities in comparison with older second-generation antipsychotics such as olanzapine or clozapine. Actually lurasidone seems to be best in terms of minimizing unwanted alterations in body weight and metabolic variables. Therapeutic drug monitoring is not strictly necessary for all of the new antipsychotic drugs because there are no unequivocal data supporting a relationship between plasma drug levels and clinical outcomes or side effects. The exception can be represented by clozapine for which plasma levels of 350-420 ng/ml are reported to be associated with an increased probability of a good clinical response. Also for olanzapine an established therapeutic range (20-50 ng/ml) is proposed to yield an optimal response and minimize side effects.

Opioids and anxiety.

The opioid system plays a crucial role in the neural modulation of anxiety. The involvement of opioid ligands and receptors in physiological and dysfunctional forms of anxiety is supported by findings from a wide range of preclinical and clinical studies, including clinical trials, experimental research, and neuroimaging, genetic, and epidemiological data. In this review we provide a summary of studies from a variety of research disciplines to elucidate the role of the opioid system in the neurobiology of anxiety. First, we report data from preclinical studies using animal models to examine the modulatory role of central opioid system on defensive responses conducive to fear and anxiety. Second, we summarize the human literature providing evidence that clinical and experimental human studies are consistent with preclinical models. The implication of these data is that activation of the opioid system leads to anxiolytic responses both in healthy subjects and in patients suffering from anxiety disorders. The role of opioids in suppressing anxiety may serve as an adaptive mechanism, collocated in the general framework of opioid neurotransmission blunting acute negative and distressing affective responses.

Clinical outcome and tolerability of duloxetine in the treatment of major depressive disorder: a 12-week study with plasma levels.

Duloxetine (DLX) is a dual serotonin and norepinephrine reuptake inhibitor that has been recently approved for the treatment of major depressive disorder (MDD). However, little is known about the relationship between DLX plasma levels and clinical response. The aims of this open-label study were 1) to assess clinical outcome and tolerability of DLX by means of clinician and patient assessments and 2) to evaluate the value of plasma DLX levels as predictors of clinical response and tolerability. This was a naturalistic, open-label study of 45 outpatients affected with MDD (16 men and 29 women), who received DLX at doses of 30-120 mg/day and were evaluated at baseline (T0) and after 2, 4 and 12 weeks (T1-3). The assessments included the Hamilton Rating Scales for Depression (HRSD) and Anxiety (HRSA), Clinical Global Impression-Severity (CGI-S), Beck's Depression Inventory (BDI) and a mood visual analogue scale (VAS). Compared with T0, there were significant improvements in HRSD at T1, T2 and T3 (P < 0.001), in HRSA, CGI-S and the self-administered BDI at T2 and T3 (P < 0.001), and in the VAS scores shown at T3 (P = 0.01). DLX treatment was safe and well tolerated. Plasma DLX levels at T2 ranged from 5 to 135 ng/mL (mean +/- SD = 53.56 +/- 39.45) and correlated almost significantly with the DLX dose (r = 0.35; P = 0.069). There was a significant curvilinear quadratic relationship between the improvement of HRSA scores and plasma DLX levels (R(2) = 0.27; P = 0.02). The incidence of anxiety or irritability was associated with the highest plasma levels. Our findings suggest that monitoring plasma DLX levels may be helpful in predicting better treatment responses and tolerability. The present data seem to suggest an optimal anxiolytic efficacy of DLX at intermediate plasma levels.

Acids in the brain: a factor in panic?

Several methods to experimentally induce panic cause profound acid-base disturbances. Evidence suggests that CO(2) inhalations, lactate infusions and, to a certain extent, voluntary hyperventilation can conceivably lead to a common scenario of brain acidosis in the face of disparate intravascular pH alterations. The importance of this event is reflected in data that support a model in which experimental panic attacks, as proxy to those occurring spontaneously, constitute a response to acute brain acidosis. Given that central CO(2)/H(+) chemoreception is an important drive for ventilation, and many chemosensitive neurons are related to respiration and arousal, this model can explain much of the connection between panic and respiration. We propose that the shared characteristics of CO(2)/H(+) sensing neurons overlap to a point where threatening disturbances in brain pH homeostasis, such as those produced by CO(2) inhalations, elicit a primal emotion that can range from breathlessness to panic.

Psychiatric diagnosis and aggression before acute hospitalisation.

OBJECTIVE: To examine the predictors of aggressive behaviours occurring before acute hospitalisation. METHODS: We analysed 350 acute admissions to a psychiatric ward during a 12-month period. The diagnoses were formulated according to the DSM IV axis I and II criteria. Aggressive behaviours occurring in the week before admission were retrospectively assessed using the modified overt aggression scale. The patients' clinical and sociodemographic variables, concurrent drug or alcohol abuse, and admission status were recorded at the time of admission. RESULTS: Aggressive and violent behaviours were highly prevalent, respectively, in 45% and 33% of the cases. Violence before admission was independently associated with drug abuse, involuntary admission status, and severe psychopathology. A diagnosis of a psychotic disorder did not increase the risk of aggression or violence, compared to the other psychiatric diagnoses. Personality disorders were significantly more associated to aggressive behaviours than psychotic disorders. CONCLUSION: The diagnosis of psychotic disorder is a poor predictor of aggression in a sample of psychiatric patients. Other clinical and non-clinical variables are associated to aggression before hospitalisation: they include drug abuse, involuntary admission status, general severity of symptoms, and diagnosis of personality disorder.

Ziprasidone outcome and tolerability: a practical clinical trial with plasma drug levels.

INTRODUCTION: The aim of this study was to evaluate clinical outcomes and the tolerability of ziprasidone in relation to its plasma levels. METHODS: Thirteen inpatients affected by schizophrenia were included in the study after an acute exacerbation phase. Ziprasidone monotherapy was administered for a period of eight weeks at a mean dose of 123.07+/-30.38 mg/day. Plasma concentrations were measured by high-performance liquid chromatography. RESULTS: Nine patients completed the study. A significant clinical improvement was observed, especially in negative symptoms ( P<0.05), and there was a significant improvement in extrapyramidal symptoms ( P<0.01). Clinical laboratory tests, such as ECG and weight, did not significantly change from baseline. Plasma ziprasidone levels ranged from 20 ng/mL to 160 ng/mL (mean: 75.8 ng/mL) and were significantly related to the improvement in negative symptoms. DISCUSSION: The study showed that ziprasidone was effective and tolerable, that use of ziprasidone was characterized by an absence of extrapyramidal symptoms and weight gain, and that no alterations in clinical laboratory tests occurred. The findings suggest a relationship between plasma levels and the clinical response to negative symptoms of schizophrenia.

Substance abuse in first-episode schizophrenic patients: a retrospective study.

Several studies suggest a high comorbidity of substance abuse and schizophrenia, associated with higher frequency of relapse, more positive symptoms and depression, cognitive impairment, poorer outcome and treatment response. A high incidence of substance abuse is also observed in first-episode patients. Among patients with substance abuse, the onset precedes the onset of psychosis of several years in most cases. All the patients with a first episode of schizophrenia, at first admission to the Psychiatric Service of Diagnosis and Treatment of Ospedale Maggiore of Milan during the years 1990 to 2004, have been included in our study.The clinical evaluation has been obtained considering the following items of Brief Psychiatric Rating Scale (BPRS): conceptual disorganization, depressed mood, hostility, hallucinations, unusual content of thought.The results showed that 34.7% of first-episode schizophrenic patients had a lifetime history of substance abuse. The age of onset of schizophrenia is significantly lower for drug abusers than for patients without any type of abuse and for alcohol abusers (p < 0.005). In multi drug abusers, cannabis resulted the most frequently used (49%), followed by alcohol (13%), and cocaine (4%). Substance abusers have obtained a significant higher score in "thought disturbance" item (p < 0.005) and in "hostility" item (p < 0.005) compared to non substance abusers. Non drug abusers showed lower mean scores of "hostility" item compared to cocaine abusers and multi drug abusers (p < 0.005). Our findings seem to indicate that substance abuse in the early course of illness determines an earlier onset of schizophrenia and increases severity of some psychotic symptoms like "hallucination" and "unusual content of thought". Therefore persons incurring a risk of schizophrenia may be warned of the possible relation between substances and psychosis and have to be counselled against the use of them.

[Disseminated intravascular coagulation in chickenpox. Report of a case in a child]. / CID in corso di varicella. Descrizione di un caso in un bambino.

The case of a healthy and immunocompetent five-year-old boy, who developed a disseminated intravascular coagulation during chickenpox is described. Disseminated intravascular coagulation manifestations were extremely severe and included macroscopic hematuria, necrotic purpura and cerebrovascular thrombosis. The outcome in this patient was a complete recovery. Nevertheless, the possibility of a seriously complicated course of chickenpox even in low-risk children subgroups suggests that the Varicella-Zoster virus infection should not be underestimated. More accurate information about the impact of chickenpox and its complications on the population is needed, in order to provide a contribution for the debate about the costs associated with this disease and the potential benefits of both the early antiviral therapy and the vaccinal prophylaxis.

Photodynamic therapy with topical delta-aminolaevulinic acid for the treatment of plantar warts.

Treatments currently employed for plantar warts are often painful (electrosurgery, cryotherapy) and not always effective (keratolytic agents). In this paper we investigate the effect of photodynamic therapy (PDT) with topical delta-aminolaevulinic acid (ALA) on plantar warts. In order to remove the superficial hyperkeratotic layer of the warts an ointment containing 10% urea and 10% salicylic acid was applied for 7 days. After gentle curettage, a cream containing 20% ALA was applied under an occlusive dressing for 5 h on 64 warts, while 57 warts (controls) received only the vehicle. Both the ALA-treated warts and the controls were irradiated using a visible light lamp (with a range of 400-700 nm, peaking at 630 nm). The light dose was 50 J/cm(2). Patients were followed-up for 22 months. Two months after the last irradiation session 48 (75.0%) out of 64 ALA-PDT treated warts had resolved. By contrast only 13 (22.8%) of the 57 control warts had done so. During the treatment a few patients complained of a mild burning sensation. The absorption of ALA by the verrucous tissue was demonstrated by in vivo fluorescence spectroscopy. This study shows that topical ALA-PDT can be an alternative treatment for plantar warts. Further studies will be necessary in order to optimize the concentration of ALA and duration of treatment.

Hypericin photosensitization of tumor and metastatic cell lines of human prostate.

We have investigated the photoactivating effect of hypericin on two cancer cell lines: PC-3, a prostatic adenocarcinoma non-responsive to androgen therapy and LNCaP, a lymphonodal metastasis of prostate carcinoma responsive to androgen therapy. The two cell lines are incubated for 24 h with hypericin at concentrations ranging from 0.001 to 0.3 microg/ml in cell culture medium. The cells are irradiated at 599 nm (fluence = 11 J/cm2) using a dye laser pumped by an argon laser. Hypericin exerts phototoxic effects on both cell lines, while it does not produce toxic effects in the absence of irradiation. These results suggest that photodynamic therapy (PDT) with hypericin could be an alternative approach to the treatment of prostatic tumors, and could be beneficial in tumors that are non-responsive to androgen therapy.

MS-2 fibrosarcoma characterization by laser induced autofluorescence.

BACKGROUND AND OBJECTIVE: MS-2 fibrosarcoma implanted in BALB-CDF1 mice was investigated by frequency and time domain measurements of the autofluorescence (AF) radiation emitted upon excitation by a N(2) laser beam (337.1 nm). STUDY DESIGN/MATERIALS AND METHODS: AF spectra were obtained by using a spectrograph, a multichannel plate and an optical multichannel analyzer for the steady state detection. Time-resolved spectra were performed by means of a monochromator, a photomultiplier, and a digital signal analyzer. RESULTS: Spectral measurements show that the autofluorescence intensity of pathologic tissue is lower than that of healthy one in the 400- to 500- spectral region. In the same spectral range, we found the fluorescence decay to be the sum of a fast and a slow component. The lifetime of the fast component of tumoral tissue is significantly lower than that of healthy samples. CONCLUSION: Frequency and time domain measurements used in combination show that MS2-fibrosarcoma is characterized by the probable presence of the free form of NADH.

[Rapid recovery from optic papillitis secondary to oto-mastoiditis in pediatric age]. / Rapida guarigione di una papillite ottica secondaria ad otomastoidite in paziente pediatrico.

In this paper we report the case of an acute papillitis of the right optic nerve secundary to a mastoiditis and sinusitis of the same site in a 10-year old boy. At onset the child presented a painful movement of the ocular globe, monolateral amaurosis and papillary oedema. The exams have confirmed the correlation among mastoiditis, sinusitis and papillitis. At the same time, we were able to exclude the presence of endocranial tumours and alteration of the other side. The child underwent a steroid therapy with a complete recovery within 30 days.

[The follow-up of a child with a syndrome due to partial deletion of chromosome 3 (p25-pter)]. / Follow-up di un bambino affetto da sindrome da delezione parziale del cromosoma 3 (p25-pter).

A case of del(3) p25-pter syndrome in a four-year-old boy whose clinical manifestations were followed and studied since birth, is described. Diagnosis was made by means of karyotype analysis. The parental chromosomes were normal. So far, only about twenty cases of this syndrome have been described in living individuals. Comparison with previously reported cases confirms that the phenotype exhibits an identifiable pattern of malformation, consisting of pre- and postnatal growth delay, typical craniofacial dysmorphisms and limb abnormalities. No severe visceral anomalies were detected in this patient. Nevertheless, the follow-up revealed a progressive decay of the psychomotor and neurosensory functions.

[Orbital cellulitis. A case report]. / Cellulite orbitaria. Descrizione di un caso clinico.

This study describes the case of a 6 years old child, male, with orbital cellulitis and underlines the importance of an early diagnosis and therapy to avoid severe complications often present in this disease. Swelling and redness of the eyelid, pain and ophthalmoplegia are the first sign of an orbital cellulitis and they require rapid diagnostic procedure such as ultrasound and TC scan of the orbital region to evaluate the integrity of the profound orbital tissues. The child was admitted at the Department of Pediatrics, University "La Sapienza" of Rome and underwent an ultrasound, TC scan and serum exams which demonstrated the elevation of the sedimentation rate, reactive C protein and WBC plus the interesting of the profound orbital tissues. The child was treated with antibiotic and antiinflammatory therapy showing a complete recovery within 7 days. An ultrasound performed 7 days later demonstrated a complete resolution of the inflammatory process. In summary, this study would like to stress the necessity of an early diagnosis and an appropriate therapy in order to avoid the severe complications often present in children with orbital cellulitis.

In vitro photo-activation of newly synthesized chlorin derivatives with red-light-emitting diodes.

We investigated the in vitro photo-activation properties of two chlorin derivatives, i.e. 8-cis-heptylchlorin dicarboxylic acid and 3-trans-heptylchlorin bisamidoglucose derivative, which exhibit lipophilic properties similar to those of the active fractions of Photofrin II, on a normal epithelial cell line (FRTL-5). We used as an irradiation source an array of diodes emitting red light (lambda = 675 nm), which produced a fluence of 7mW cm-2 on the cells. We found that photo-activation with chlorin derivatives in the concentration range 1-100 ng ml-1 greatly enhanced the mortality of the irradiated cells (energy density, 0.25 J cm-2) with respect to the control cells kept in the dark. This response is immediate and appears to be an "all or none' effect. Taking into account that compounds exhibit a strong absorbance peak in the long wavelength region of visible light where tissues are relatively transparent, our results suggest that chlorins can be considered to be good candidates for application in photodynamic therapy.