Synthesis and pharmacological investigation of beta-substituted pyrrolo derivatives

A series of pyrroles bearing an ethanol- or an iso-propanolamine side-chain in the beta-position was prepared and their adrenergic activity evaluated. The absence of any appreciable activity suggests that the pyrrole ring is not suitable for replacing the phenol nucleus in derivatives possessing an adrenergic activity. Noteworthy is the amphetamine-like activity observed in amino-ketone (XXIII).     

Preclinical hypogonadism in genetic hemochromatosis in the early stage of the disease: evidence of hypothalamic dysfunction.

We studied endocrine functions at baseline and after TRH and LHRH stimulation in a group of 7 young male patients with genetic hemochromatosis (HE) without liver damage (i.e. fibrosis and cirrhosis). In five patients endocrine re-evaluations after complete iron depletion was also performed. Mean basal testosterone (T), FSH, LH and PRL were significantly lower than in controls. Serum T increased normally after HCG stimulation. The normal or high increments of LH after LHRH stimulation suggest that secretion capacity of LH was intact and that hypothalamic dysfunction could be responsible for the preclinical gonadal deficiency found in our patients. The response of PRL to TRH indicates that secretion capacity of lactotrophs although present, was decreased and did not improve after phlebotomy therapy. After iron depletion the two patients with the lowest basal T levels showed the highest increments indicating that in the early stages of hypothalamic-pituitary damage gonadal dysfunction is still reversible in HE patients.     

Efficacy in intra-oesophageal acid suppression may decrease after 2-year continuous treatment with proton pump inhibitors

BACKGROUND: Long-term intra-oesophageal acid suppression with proton pump inhibitors represents a management option for Barrett's oesophagus and severe reflux oesophagitis, but its stability over time has not been adequately assessed. AIM: Our aim was to evaluate prospectively the efficacy of proton pump inhibitors in suppressing intra-oesophageal acidity after 2-year continuous treatment. METHODS: Forty-five patients with Barrett's oesophagus or severe reflux oesophagitis on a proton pump inhibitor regimen (once or twice daily) that normalised the total percentage acid exposure time were re-evaluated by means of 24-h oesophageal pH-monitoring after 2-year of continuous unmodified treatment. RESULTS: A significant rise in the total percentage acid exposure time was observed at 2-year follow-up (P=0.029), owing to an increased value in 27 (60%) cases (9 on a twice daily regimen), higher than normal in 10 of them (22% of the whole group) (3 on a twice daily regimen). In 18 patients (40%) the total percentage acid exposure time was stable or decreased. Heartburn remained efficiently suppressed in all patients. CONCLUSIONS: The efficacy of proton pump inhibitors in suppressing intra-oesophageal acidity during continuous treatment may decrease over time, up to abnormal levels of oesophageal acid exposure in a minority of cases. This may occur without heartburn recurrence and with both once and twice daily regimens.     

Scapulothoracic motion in normal shoulders and shoulders with glenohumeral instability and impingement syndrome. A study using Moiré topographic analysis.

Qualitative visual inspection and manual muscle testing are traditional methods of evaluation that may overlook subtle weakness of the axioscapular musculature. A modification of the standard technique of Moiré topographic analysis of spinal deformity was applied to assess axioscapular muscle function in 51 subjects: 22 asymptomatic individuals, 22 with shoulder instability, and seven with impingement syndrome. Static Moiré evaluation demonstrated scapulothoracic asymmetry or increased topography in 14% of asymptomatic subjects, compared with 32% and 57% in the instability and impingement groups, respectively. The dynamic Moiré test demonstrated an abnormal Moiré pattern in 18% of asymptomatic individuals, compared with 64% and 100% in the instability and impingement groups, respectively. Axioscapular muscle dysfunction is common with both instability and impingement syndrome of the shoulder, although it remains to be determined whether this represents a primary or secondary phenomenon.     

Histological comparison of implanted cadaveric and porcine dermal matrix grafts.

OBJECTIVES: Histological comparison of human-based (AlloDerm) and porcine-based (ENDURAGen) dermal matrices regarding tissue incorporation and neovascularization as potential soft tissue augmentation materials. STUDY DESIGN: In vivo, rat model. METHODS: Subcutaneous implantation of 1-mm thick, 1 cm x 1 cm pieces of AlloDerm, ENDURAGen, and meshed ENDURAGen was performed in 24 Sprague Dawley rats. Implant materials were harvested at 4 (n = 12) and 8 weeks (n = 12). Histological quantification of soft tissue ingrowth and microvascular density was performed following hematoxylin-eosin staining and CD34 immunohistochemistry, respectively. RESULTS: AlloDerm showed significantly greater soft tissue ingrowth and microvascular density compared with both ENDURAGen and meshed ENDURAGen at 4 and 8 weeks (P < 0.001). CONCLUSIONS: Although these results may differ in human host tissues, AlloDerm seems to be a more suitable dermal matrix implant than ENDURAGen for cases in which tissue incorporation and neovascularization are sought for the optimal outcome based on this animal model.     

Age-dependent cerebral metabolic effects of unilateral nucleus basalis magnocellularis ablation in rats

To investigate the age-dependent functional importance of cholinergic neocortical inputs, and to explore whether cortical cholinergic denervation in aged animals might better model the cerebral metabolic changes of Alzheimer's disease, the effects of unilateral ablation of the nucleus basalis magnocellularis (NBM) on cerebral glucose metabolism were studied in young and aged rats. Regional cerebral metabolic rates for glucose (rCMRglc) were determined, using the [14C]deoxyglucose method, in 48 brain regions of 3- and 24-month old Fischer-344 rats at 3, 7, 14 and 28 days after stereotaxic injection of ibotenate into the right NBM, and in sham-operated animals at 3 and 14 days later. For both ages the peak effect of unilateral NBM ablation occurred 3 days later: in young rats, rCMRglc was significantly reduced (compared to the contralateral side) in all 24 anterior cortical areas examined (mean decline 20%), whereas in aged animals, only 9 of 24 areas showed a significant decline in glucose utilization, and the magnitude of rCMRglc reduction (9%) was smaller. Near complete recovery of rCMRglc occurred by 7 days in young and old rats. We conclude that the basalocortical cholinergic projection plays a smaller role in neocortical function of aged rats, possibly because its tonic activity is reduced. Both young and aged rats undergo cortical metabolic normalization after unilateral NBM ablation; hence the NBM-lesioned aged rat is not a better model of the progressive decline in rCMRglc that occurs in Alzheimer's disease.     

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.