Is aceruloplasminemia treatable? Combining iron chelation and fresh-frozen plasma treatment.

We report the case of a patient with hereditary ceruloplasmin deficiency due to a novel gene mutation in ceruloplasmin gene (CP), treated with fresh frozen plasma (FFP) and iron chelation therapy. A 59-year-old man with a past history of diabetes was admitted to our department due to progressive gait difficulties and cognitive impairment. Neurological examination revealed a moderate cognitive decline, with mild extrapyramidal symptoms, ataxia, and myoclonus. Brain T2-weighted MR imaging showed bilateral basal ganglia hypointensity with diffuse iron deposition. Increased serum ferritin, low serum copper concentration, undetectable ceruloplasmin, and normal urinary copper excretion were found. The genetic analysis of the CP (OMIM #604290) reported compound heterozygosity for two mutations, namely c.848G > A and c.2689_2690delCT. Treatment with FFP (500 mL i.v./once a week) and administration of iron chelator (Deferoxamine 1000 mg i.v/die for 5 days, followed by Deferiprone 500 mg/die per os) were undertaken. At the 6-month follow-up, clinical improvement of gait instability, trunk ataxia, and myoclonus was observed; brain MRI scan showed no further progression of basal ganglia T2 hypointensity. This case report suggests that the early initiation of combined treatment with FFP and iron chelation may be useful to reduce the accumulation of iron in the central nervous system and to improve the neurological symptoms.

Clinical pharmacology and vascular risk.

Pharmacological treatment and several drugs of abuse have been associated with ischemic heart disease (IHD) and cerebrovascular diseases (CVD). However, there is a paucity of data on the independent risk of vascular disease (VD) associated with pharmacological treatment and no controlled trials demonstrating a reduction in risk with abstinence. Information about IHD and CVD-related drug abuse is mainly limited to epidemiological studies focused on urban populations. The potential link between some pharmacological treatments (estrogen, some oncologic drugs and some atypical antipsychotics) and cerebrovascular adverse events was analyzed, but disagreement about an association persists. Drugs of abuse, including cocaine, amphetamines and heroin, have been associated with an increased vascular risk. These drugs can cause abrupt changes in blood pressure, vasculitic-type changes, lead to embolization caused by infective endocarditis, and hemostatic and hematologic abnormalities that can result in increased blood viscosity and platelet aggregation. Long-term treatment strategies based on medication, psychological support, and outreach programs play an important role in treatment of drug dependency. In these last years public interest in risk factors for VD has been constantly increasing and the successful identification and management of pharmacological treatment and drug abuse can be challenging. One of the major public health issues for the future will be to focus more on new vascular risk factor recognition and management. The objective of this chapter is to review the relevance of IHD and CVD associated with various pharmacological treatments and drug abuse with focusing on ischemic disease. This chapter reports the clinical evidence of this association and analyzes the experimental role of new drugs as a growing risk factor of VD with the hypothetical new association. In conclusion, in this chapter great attention is paid to evaluating the scientific and real evidence of cerebrovascular effect and drug use and abuse so as to identify a new groups of "modifiable" risk factors.

Mild hyperhomocysteinemia is a risk-factor in all etiological subtypes of stroke.

The role of hyperhomocysteinemia as independent risk factor for stroke needs to be confirmed. The aims of our study were to assess (i) the association between risk of stroke and increasing values of plasma homocysteine and (ii) the interaction between mild hyperhomocysteinemia and conventional vascular risk factors. We studied 161 consecutive patients with first-ever ischemic stroke classified using TOAST criteria and 152 neurologically healthy controls. Homocysteine was measured using high performance liquid chromatography (HPLC). Homocysteinemia was elevated in all stroke subtypes: 13.0+/-2.5 micromol/l in patients with cardioembolic disease, 13.9+/-5.4 micromol/l in those with small vessel diseases, 15.5+/-6.8 micromol/l in cases of undetermined stroke, and 17.8+/-13.5 micromol/l in patients with large vessel disease. Mean homocysteinemia was 8.10 micromol/l (SD=2.5) in controls. The logistic regression analysis showed that important independent risk factors for ischemic stroke were hypertension (p<0.0001; OR= 3.205; 95% CI, 1.788-5.742), hyperhomocysteinemia (p<0.0001; OR=1.425; 95% CI, 1.300-1562) and hyperlipidemia (p=0.018; OR=2.243; 95% CI, 1.147-4.385). Hyperhomocyst(e)inemia is an independent risk factor for all stroke subtypes and should be routinely measured and treated in stroke patients.

Cerebrospinal fluid biochemical markers in early detection and in differential diagnosis of dementia disorders in routine clinical practice.

Measurement of total tau and amyloid beta1-42 (Ab42) in cerebrospinal fluid (CSF) improves diagnostic accuracy of Alzheimer's disease (AD). We examined a consecutive patient sample referred to our center for diagnostic assessment of cognitive decline. CSF tau and Abeta42 were assayed each week as routine neurochemical analyses. There were 119 patients investigated. These included 61 with probable AD (35 mild AD, 26 severe AD), 24 with mild cognitive impairment (MCI), 14 with vascular dementia, 11 with Lewy body dementia, and 9 with fronto-temporal dementia. Mild AD showed significantly lower CSF Abeta42 levels and significantly higher CSF tau levels than the other diagnostic groups; 79% of MCI patients had pathological values for both biomarkers. We confirm that these biomarkers have a role in the clinical work-up of patients with cognitive deficits.

Cerebrospinal fluid levels of biomarkers and activity of acetylcholinesterase (AChE) and butyrylcholinesterase in AD patients before and after treatment with different AChE inhibitors.

In order to evaluate the biochemical effects of long-term treatment with inhibitors of acetylcholinesterase (AChE) in patients with Alzheimer's disease (AD), we measured the activities of AChE and butyrylcholinesterase (BuChe) and the concentrations of beta-amyloid (1-42), tau and phosphorylated tau proteins in the cerebrospinal fluid (CSF). A total of 91 patients suffering from probable AD of mild to moderate degree were treated for 6 months with donepezil (n=59), galantamine (n=15), rivastigmine (n=10), or placebo (n=7). AChE activity in CSF was significantly increased after treatment with donepezil and galantamine; the opposite was observed in the rivastigmine-treated group. Untreated patients did not show any AChE activity variation. BuChE did not show any change in any of the groups studied. Mean values of beta-amyloid(1-42), total tau and phosphorylated tau also did not vary significantly. We conclude that AChE inhibitors induce different effects on CSF AChE activity, while other CSF biomarkers are not significantly affected by treatment.

Plasma total homocysteine levels and the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene: a study in an Italian population with dementia.

Hyperhomocysteinemia is a known risk factor for vascular disease and commonly occurs in the elderly. Several studies have shown an association between elevated plasma homocysteine levels and cognitive impairment, indicating that it may play a role in the pathophysiology of dementia. We studied plasma homocysteine, folate, vitamin B12 levels and the MTHFR C677T genotype in an Italian population of patients with dementia. We confirmed that elevated plasma tHcy (>14 micromol/l) is common in elderly subjects with dementia. Although we found a high prevalence of the MTHFR TT genotype (21.2%) the allele frequency is not over-represented relative to the control population. We also observed a high incidence of folate deficiency (38%) in subjects with dementia. Elevated homocysteine was associated with low plasma folate (<5.7 nmol/l) and the MTHFR TT genotype. Moderate to severe hyperhomocysteinemia (>26.1 nmol/l) was associated with a significantly lower MMSE score. Hyperhomocysteinemia may be neurotoxic by several different mechanisms affecting cognitive function. Further studies are needed to fully explore the potential of B vitamin supplementation to lower plasma homocysteine and improve cognitive function.

Cerebrospinal fluid acetylcholinesterase activity after long-term treatment with donepezil and rivastigmina.

At present acetylcholinesterase (AChE) inhibitors (AChEIs) represent the only reliable therapeutic resource for symptomatic treatment of Alzheimer Disease (AD). This study was designed to assess the effects of 6-12 month treatment with AChEIs donepezil and rivastigmine on cerebrospinal fluid (CSF) AChE and butyrylcholinesterase (BuChE) activity in AD patients. The pattern of AChE isoforms (G4, G1, G2) before and after treatment was investigated as well. In AD patients treated with donepezil a significant increase of CFS AChE activity was observed, whereas treatment with rivastigmine induced a significant decrease of AChE activity. Both drugs did not change BuChE activity and tended to restore the physiological pattern of AChE isoform. The possible significance of the influence of AChEIs on CSF AChE activity and isoforms is discussed.

Pharmacological treatment of non-cognitive disturbances in dementia disorders.

Behavioral and psychological symptoms of dementia (BPSD) occur in 50-90% of patients with Alzheimer's disease (AD). They cause premature institutionalization, increased costs of care and significant loss of quality-of-life for the patient and his/her family and caregivers. Non-pharmacological interventions are first-line in dealing with milder BPSD, while for moderate to severe BPSD, medication is clearly indicated in conjunction with non-pharmacological interventions. An imbalance of different neurotransmitters (acetylcholine, dopamine, noradrenaline, serotonin) has been proposed as the neurochemical correlate of BPSD. An involvement of some specific brain regions responsible for emotional activities (parahippocampal gyrus, dorsal raphe, locus coeruleus) and cortical hypometabolism have been suggested to contribute to BPSD. Atypical or novel antipsychotic drugs represent the reference drugs for treating BPSD. Among these, risperidone is considered as a drug of choice. Also, selective serotonin reuptake inhibitors (SSRIs) are useful in the treatment of BPSD.

CSF phosphorylated tau is a possible marker for discriminating Alzheimer's disease from dementia with Lewy bodies. Phospho-Tau International Study Group.

Tau and beta-amyloid (1-42) (Abeta42) are two independent markers for the early diagnosis of Alzheimer's disease (AD). In the present study, biochemical markers were validated as tools for differential diagnosis between AD and dementia with Lewy bodies (DLB). Tau, Abeta42 and phospho-tau (181P) were measured in cerebrospinal fluid (CSF) from controls (n=40) and from patients with AD (n=80) or DLB (n=43) using the HT7-AT270 assay (prototype version). In comparison with AD, in DLB no differences were found for Abeta42 and lower phospho-tau. ROC analysis was used to compare the discriminatory power of total tau with that of phospho-tau. The area under the curve (AUC) amounted to 0.782 +/- 0.048 (mean +/- SE) for tau and to 0.839 +/- 0.042 for phospho-tau (p = 0.039) for differentiation of AD from DLB. The present results indicate that CSF phospho-tau may be a good marker for differentiation between AD and DLB.

[Gastric duplication of 3 observations]. / Duplicación gástrica a propósito de tres observaciones.

Gástric duplicación si an infrequent congenital malformation present in both, neonatal period and childhood, and exceptionally during adulthood. We present here there cases of gastric duplication from patients of different ages, in which it was not possible to make diagnosis before surgery. In all of them cystic form was the predominating one, without communication with gastric lumen (cavity). Diagnosis was performed after laparotomy and histopathological examination.

Duplicación gástrica a propósito de tres observaciones / Gastric duplication of 3 observations

Gastric duplicacion si an infrequent congenital malformation present in both, neonatal period and childhood, and exceptionally during adulthood. We present here there cases of gastric duplication from patients of diferent ages, in wich it was not possible to make diagnosis before surgery. In all of them cystic form was the predominating one, without communication with gastric lumen (cavity). Diagnosis was performed after laparotomy and histopathological examination.

[Propafenone and verapamil poisoning. Report of 2 clinical cases]. / Intossicazione da propafenone e verapamil. Descrizione di due casi clinici.

We described the self-poisoning of two young adolescents who took improper doses of two major cardiovascular drugs: propafenone and verapamil. The young girls developed markedly different clinical patterns: ECG abnormalities without clinical consequences were found in one case progressively ingravescent ECG abnormalities leading to cardiac arrest in the other. These differences are probably due to varying doses taken and metabolic states. Conventional detoxication and resuscitation techniques proved successful in both cases.

Local renin-angiotensin system in human adrenals and aldosteronomas.

The local renin-angiotensin system may regulate adrenal cell growth and function. Angiotensinogen, renin, and angiotensin converting enzyme gene expression were studied in four normal adrenal glands (removed from patients with renal carcinomas) and five aldosterone-secreting adenomas. Northern blot analysis showed expression of angiotensinogen messenger RNA (mRNA) in normal adrenals at levels approximately 35-fold lower than liver and sixfold lower than kidney. Similar angiotensinogen mRNA levels were present in two aldosteronomas, whereas a third had levels approximately 50% of those found in kidney. Renin mRNA was detectable in most normal adrenals and in three adenomas, one of which had relatively high renin mRNA levels. Angiotensin converting enzyme gene was expressed in adrenal tissue and in three adenomas. Portions from these normal adrenals and two of these aldosteronomas, as well as samples from two other adrenals and three aldosteronomas, were also studied in an in vitro superfusion system coupled with active renin radioimmunometric assay, angiotensin II/III, and aldosterone radioimmunoassay. Total amounts of active renin and angiotensin II/III released from normal adrenals during 270 minutes of superfusion were higher than the amounts released from aldosteronomas (312 +/- 35 versus 187 +/- 43 and 823 +/- 100 versus 436 +/- 55 pg/100 mg tissue, respectively; mean +/- SEM, p less than 0.05), whereas aldosterone release from the adenomatous tissue was approximately threefold higher (320 +/- 21 versus 115 +/- 18 ng/100 mg tissue; mean +/- SEM, p less than 0.01). Total amounts of active renin and angiotensin II/III released by normal or adenomatous adrenal samples exceeded threefold to fourfold the amounts extracted from similar samples of the same surgical specimen.(ABSTRACT TRUNCATED AT 250 WORDS)

Fibrosis hepatica y progesterona

Con el fin de estudiar la acción de la Prog sobre la fibrosis hepática, fue inducida esta alteración por medio de la ingesta de C14C y etanol, en 55 conejos, entre 1 y 2 años, raza New Zealand; desarrolando la fibrosis en 6 meses. El grupo de animales tratados con Prog, ya sea desde el comienzo o después de 180 días de recibir el tóxico, presentaba disminución o menos fibrosis; así como protección del hepatocito, que se evidenciaba por la nobalonización o vacuolización de las células, no infiltrado inflamatorio, ni tampoco metamorfosis grasa. Si algunas de estas alterraciones habían aparecido, al iniciar el tratamiento con Prog disminuían gradualmente hasta desaparecer. Los datos de laboratorio tuvieron una diferencia altamente significativa a los 60 y 180 días entre los grupos que recibían el tóxico y los que revibían Prog, ya sea desde el comienzo o diferida. La Prog, como se ha visto en cultivos de fibroblastos fetales y en el tratamiento de tumores desmoides o adhesiones quirúrgicas, destruye los fibroblastos y por consiguiente disminuye el tamaño de estos tumores y la cohesión de las adherencias. La razón de no haberse hallado una resolución total de la cirrosis (aunque si una disminución manifiesta de la fibrosis) puede deberse a la actividad de miofibroblastos que provocan la retracción del tejido hepático dañado

[Hepatic fibrosis and progesterone]. / Fibrosis hepática y progesterona.

To study the progesterone (Prog.) action on the hepatic fibrosis, we produced fibrosis on 55 New Zealand male rabbits, by oral ingestion of carbon tetrachloride (Cl4C) and ethanol. They developed it in six months. All the animals received the toxic. A group of these animals also received the Prog since the onset (0.66 mg/3 times a week, IM) and the rest received it 180 days after the beginning of the experiment. We could see in the biopsies of the animals who received Prog since the beginning or after 180 days: protection of the hepatocytes, no vacuolization of the cell, no inflammatory infiltrate, no fat metamorphosis, very thin fibrous hands. If one of these alterations had appeared with the toxic, the Prog action would have diminished it gradually until its disappearance. Between the groups who received only toxic and the groups that received th Prog (at the beginning or deferred), the laboratory results showed a high significative difference (p less than o.01) especially in the transferases (ASAT-ALAT) in the 60-180 days period. The Prog in the fibroblasts culture and in the treatment of desmoid tumours, on operative adhesions, destroy the fibroblasts and for this action diminished the volume of the tumour and the adhesions. Perhaps the incomplete resolution of the cirrhosis (though the hands of fibrosis diminished considerably) could be explained by the activity of another kind of fibroblast (the myofibroblast), which provokes the retraction of cirrhotic hepatic tissue.

Growth inhibition of fibroblasts by progesterone and medroxyprogesterone in vitro.

This study was carried out to evaluate in vitro the beneficial effects observed in various aggressive fibromatoses (mediastinal, retroperitoneal, paraneoplastic fibrosis and desmoid tumors) after treatment with progesterone. Primary cultures of fibroblasts were prepared from fetuses of Swiss strain mice. Continuous fibroblast lines LM and Vero were also used. Moreover, cultures of non-fetal human fibroblast from skin and lung were employed. Epithelial tumor cell line HeLa was used as a control. All cultures were incubated with various doses of progesterone at concentrations from 1.4 X 10(-4) to 1.4 X 10(-3) M. Human cells and monolayers of fetal murine fibroblast were submitted to the action of medroxyprogesterone solution at the same concentrations as used for progesterone. Other steroids (estrone, estriol, testosterone and prednisolone) were used at the identical concentrations in the same vehicles. Progesterone affected all lines of fibroblasts studied and destroyed them within either 2-4 or 24-48 h depending on the steroid concentrations used. Medroxyprogesterone had a comparable effect on human cell lines and monolayers of fetal murine fibroblasts provided that the same ratio between the hormone concentration and the time of exposure was maintained. With higher medium concentrations shorter times of incubation were required for the destruction of fibroblast. However, to observe a degree of lysis similar to that elicited by progesterone, it was necessary to use 4 times higher concentrations of medroxyprogesterone. No effect on HeLa epithelial cells was observed nor were the controls affected by the steroids or diluents used at the appropriate concentrations. Results from incubation studies using monolayers of murine fibroblast and 14C-progesterone suggested that the cells were destroyed by the progesterone and not by a bioproduct of its metabolism.