Predicting COPD 1-year mortality using prognostic predictors routinely measured in primary care.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of mortality. Patients with advanced disease often have a poor quality of life, such that guidelines recommend providing palliative care in their last year of life. Uptake and use of palliative care in advanced COPD is low; difficulty in predicting 1-year mortality is thought to be a major contributing factor. METHODS: We identified two primary care COPD cohorts using UK electronic healthcare records (Clinical Practice Research Datalink). The first cohort was randomised equally into training and test sets. An external dataset was drawn from a second cohort. A risk model to predict mortality within 12 months was derived from the training set using backwards elimination Cox regression. The model was given the acronym BARC based on putative prognostic factors including body mass index and blood results (B), age (A), respiratory variables (airflow obstruction, exacerbations, smoking) (R) and comorbidities (C). The BARC index predictive performance was validated in the test set and external dataset by assessing calibration and discrimination. The observed and expected probabilities of death were assessed for increasing quartiles of mortality risk (very low risk, low risk, moderate risk, high risk). The BARC index was compared to the established index scores body mass index, obstructive, dyspnoea and exacerbations (BODEx), dyspnoea, obstruction, smoking and exacerbations (DOSE) and age, dyspnoea and obstruction (ADO). RESULTS: Fifty-four thousand nine hundred ninety patients were eligible from the first cohort and 4931 from the second cohort. Eighteen variables were included in the BARC, including age, airflow obstruction, body mass index, smoking, exacerbations and comorbidities. The risk model had acceptable predictive performance (test set: C-index = 0.79, 95% CI 0.78-0.81, D-statistic = 1.87, 95% CI 1.77-1.96, calibration slope = 0.95, 95% CI 0.9-0.99; external dataset: C-index = 0.67, 95% CI 0.65-0.7, D-statistic = 0.98, 95% CI 0.8-1.2, calibration slope = 0.54, 95% CI 0.45-0.64) and acceptable accuracy predicting the probability of death (probability of death in 1 year, n high-risk group, test set: expected = 0.31, observed = 0.30; external dataset: expected = 0.22, observed = 0.27). The BARC compared favourably to existing index scores that can also be applied without specialist respiratory variables (area under the curve: BARC = 0.78, 95% CI 0.76-0.79; BODEx = 0.48, 95% CI 0.45-0.51; DOSE = 0.60, 95% CI 0.57-0.61; ADO = 0.68, 95% CI 0.66-0.69, external dataset: BARC = 0.70, 95% CI 0.67-0.72; BODEx = 0.41, 95% CI 0.38-0.45; DOSE = 0.52, 95% CI 0.49-0.55; ADO = 0.57, 95% CI 0.54-0.60). CONCLUSION: The BARC index performed better than existing tools in predicting 1-year mortality. Critically, the risk score only requires routinely collected non-specialist information which, therefore, could help identify patients seen in primary care that may benefit from palliative care.

Elderly patients with multimorbidity in the home setting: umbrella review on therapeutic non-adherence causes.

OBJECTIVE: The elderly population is the most at risk regarding adherence, especially in the coexistence of multiple diseases. This study aims to detect factors contributing to therapeutic non-adherence in elderly patients in home settings. MATERIALS AND METHODS: A review protocol was developed to conduct the umbrella review using the methodological framework of the Richardson et al study. The search strategy was developed in December 2022 to conduct a systematic search and to perform an Umbrella Review of systematic reviews, meta-analyses and integrative reviews published from 2012 to 2022 in English. RESULTS: A total of 26,038 articles were identified and screened. 18 relevant articles were included in the study. CONCLUSIONS: Therapeutic adherence in elderly patients with comorbidities in polypharmacotherapy at home is a significant problem in public health and health care. Several factors of non-adherence have been identified in the studies reviewed, confirming that the problem is multifactorial. Reducing the number of medications prescribed would appear optimal, although often not possible, as this has been seen to have an immediate positive impact. A multidisciplinary approach makes it possible not to fragment care, ensuring positive feedback on therapeutic adherence.

Early-versus-Late Endovascular Stroke Treatment: Similar Frequencies of Nonrevascularization and Postprocedural Cerebrovascular Complications in a Large Single-Center Cohort Study.

BACKGROUND AND PURPOSE: Endovascular treatment of acute ischemic stroke is now performed more frequently in the late window in radiologically selected patients. However, little is known about whether the frequency and clinical impact of incomplete recanalization and postprocedural cerebrovascular complications differ between early and late windows in the real world. MATERIALS AND METHODS: We retrospectively reviewed all patients with acute ischemic stroke receiving endovascular treatment within 24 hours from 2015 to 2019 and included in the Acute STroke Registry and Analysis of Lausanne. We compared rates of incomplete recanalization and postprocedural cerebrovascular complications (parenchymal hematoma, ischemic mass effect, and 24-hour re-occlusion) in the early (<6 hours) versus late window (6-24 hours, including patients with unknown onset) populations and correlated them with the 3-month clinical outcome. RESULTS: Among 701 patients with acute ischemic stroke receiving endovascular treatment, 29.2% had late endovascular treatment. Overall, incomplete recanalization occurred in 56 patients (8%), and 126 patients (18%) had at least 1 postprocedural cerebrovascular complication. The frequency of incomplete recanalization was similar in early and late endovascular treatment (7.5% versus 9.3%, adjusted P =.66), as was the occurrence of any postprocedural cerebrovascular complication (16.9% versus 20.5%, adjusted P = .36). When analyzing single postprocedural cerebrovascular complications, rates of parenchymal hematoma and ischemic mass effect were similar (adjusted P = .71, adjusted P = .79, respectively), but 24-hour re-occlusion seemed somewhat more frequent in late endovascular treatment (4% versus 8.3%, unadjusted P = .02, adjusted P = .40). The adjusted 3-month clinical outcome in patients with incomplete recanalization or postprocedural cerebrovascular complications was comparable between early and late groups (adjusted P = .67, adjusted P = .23, respectively). CONCLUSIONS: The frequency of incomplete recanalization and of cerebrovascular complications occurring after endovascular treatment is similar in early and well-selected late patients receiving endovascular treatment. Our results demonstrate the technical success and safety of endovascular treatment in well-selected late patients with acute ischemic stroke.

Predictors of Endovascular Treatment Procedural Complications in Acute Ischemic Stroke: A Single-Center Cohort Study.

BACKGROUND AND PURPOSE: Procedural complications occur in 4%-29% of endovascular treatments in acute ischemic stroke. However, little is known about their predictors and clinical impact in the real world. We aimed to investigate the frequency and clinical impact of procedural complications of endovascular treatment and identify associated risk factors. MATERIALS AND METHODS: From 2015-2019, we retrospectively reviewed all patients with acute ischemic stroke receiving endovascular treatment within 24 hours included in the Acute STroke Registry and Analysis of Lausanne. We identified patients having an endovascular treatment procedural complication (local access complication, arterial perforation, dissection or vasospasm, and embolization in a previously nonischemic territory) and performed logistic regression analyses to identify associated predictors. We also correlated procedural complications with long-term clinical outcome. RESULTS: Of the 684 consecutive patients receiving endovascular treatment, 113 (16.5%) had at least 1 procedural complication. The most powerful predictors were groin puncture off-hours (OR = 2.24), treatment of 2 arterial sites (OR = 2.71), and active smoking (OR = 1.93). Patients with a complication had a significantly less favorable short-term clinical outcome (Δ-NIHSS score of -2.2 versus -4.33, P-value adjusted < .001), but a similar long-term clinical outcome (mRS at 3 months = 3 versus 2, P-value adjusted = .272). CONCLUSIONS: Procedural complications are quite common in endovascular treatment and lead to a less favorable short-term but similar long-term outcome. Their association with treatment off-hours and at 2 arterial sites requires particular attention in these situations to optimize the overall benefit of endovascular treatment.

2-pentadecyl-2-oxazoline prevents cognitive and social behaviour impairments in the Amyloid ß-induced Alzheimer-like mice model: Bring the α2 adrenergic receptor back into play.

The 2-pentadecyl-2-oxazoline (PEA-OXA) is a natural compound with protective action in neuro-inflammation. We have previously shown that PEA-OXA behaves as an α2 adrenergic receptor (α2AR) antagonist and a putative protean agonist on histamine H3 receptors. Recently, neuroinflammation and monoaminergic neurotransmission dysfunction has drawn particular attention in Alzheimer Disease (AD) pathophysiology. In this context, the objective of this study was to investigate the effects of the dual-acting PEA-OXA in an AD-like model in mice. A combined computational and experimental approach was used to evaluate the ability of PEA-OXA to bind α2A-AR subtype, and to investigate the effects of PEA-OXA treatment on neuropathological (behavioural and functional) effects induced by soluble Amyloid ß 1-42 (sAß1-42) intracerebroventricular injection. Computational analysis revealed the PEA-OXA ability to bind the α2A-AR, a pharmacological target for AD, in two alternative poses, one overlapping the Na+ binding site. In vivo studies indicated that chronic treatment with PEA-OXA (10 mg/kg, os) restored the cognitive (discriminative and spatial memory) deficits and social impairments induced by sAß injection. Consistently, electrophysiological analysis showed a recovery of the long-term potentiation in the hippocampus (Lateral Entorhinal Cortex-Dentate Gyrus pathway), while neuroinflammation, i.e., increased pro-inflammatory cytokines levels and microglia cells density were reduced. These data provide the basis for further investigation of the pro-cognitive aptitude of PEA-OXA by proposing it as an adjuvant in the treatment in AD, for which the available pharmacological approaches remain unsatisfactory. Moreover, this study offers new future direction in research investigating the role of α2AR in neuropsychiatric illness and therapies.

Correlation between ASPECTS and Core Volume on CT Perfusion: Impact of Time since Stroke Onset and Presence of Large-Vessel Occlusion.

BACKGROUND AND PURPOSE: Both ASPECTS and core volume on CTP are used to estimate infarct volume in acute ischemic stroke. To evaluate the potential role of ASPECTS for acute endovascular treatment decisions, we studied the correlation between ASPECTS and CTP core, depending on the timing and the presence of large-vessel occlusion. MATERIALS AND METHODS: We retrospectively reviewed all MCA acute ischemic strokes with standardized reconstructions of CTP maps entered in the Acute STroke Registry and Analysis of Lausanne (ASTRAL) registry. Correlation between ASPECTS and CTP core was determined for early (<6 hours) versus late (6-24 hours) times from stroke onset and in the presence versus absence of large-vessel occlusion. We used correlation coefficients and adjusted multiple linear regression models. RESULTS: We included 1046 patients with a median age of 71.4 years (interquartile range, IQR = 59.8-79.4 years), an NIHSS score of 12 (IQR, 6-18), an ASPECTS of 9 (IQR, 7-10), and a CTP core of 13.6 mL (IQR, 0.6-52.8 mL). The overall correlation between ASPECTS and CTP core was moderate (ρ = -0.49, P < .01) but significantly stronger in the late-versus-early window (ρ = -0.56 and ρ = -0.48, respectively; P = .05) and in the presence versus absence of large-vessel occlusion (ρ = -0.40 and ρ = -0.20, respectively; P < .01). In the regression model, the independent association between ASPECTS and CTP core was confirmed and was twice as strong in late-arriving patients with large-vessel occlusion (ß = -0.21 per 10 mL; 95% CI, -0.27 to -0.15; P < .01) than in the overall population (ß = -0.10; 95% CI, -0.14 to -0.07; P < .01). CONCLUSIONS: In a large cohort of patients with acute ischemic stroke, we found a moderate correlation between ASPECTS and CTP core. However, this was stronger in patients with large-vessel occlusion and longer delay from stroke onset. Our results could support the use of ASPECTS as a surrogate marker of CTP core in late-arriving patients with acute ischemic stroke with large-vessel occlusion.

Mutation of a bHLH transcription factor allowed almond domestication.

Wild almond species accumulate the bitter and toxic cyanogenic diglucoside amygdalin. Almond domestication was enabled by the selection of genotypes harboring sweet kernels. We report the completion of the almond reference genome. Map-based cloning using an F1 population segregating for kernel taste led to the identification of a 46-kilobase gene cluster encoding five basic helix-loop-helix transcription factors, bHLH1 to bHLH5. Functional characterization demonstrated that bHLH2 controls transcription of the P450 monooxygenase-encoding genes PdCYP79D16 and PdCYP71AN24, which are involved in the amygdalin biosynthetic pathway. A nonsynonymous point mutation (Leu to Phe) in the dimerization domain of bHLH2 prevents transcription of the two cytochrome P450 genes, resulting in the sweet kernel trait.

New evidences for old biomarkers: effects of several xenobiotics on EROD and AChE activities in Zebra mussel (Dreissena polymorpha).

The biomarker approach is widely used both in vertebrates and invertebrates for environmental biomonitoring, because it can supply an integrated response for multi-xenobiotics contamination. However, the use of biomarkers requires the identification of every possible variation that can influence the biochemical response, because ecosystems are generally subject to a mixture of pollutants, which can create additive, opposite or competitive effects. In recent years, there has been considerable interest in the use of biomarkers within marine bivalves, while very few data are available for freshwater molluscs. The aim of this research was to investigate changes on EROD and AChE activities in the freshwater bivalve Zebra mussel (Dreissena polymorpha) exposed to different pollutants (Arochlor 1260, CB 153 and 126, pp'DDT, chlorpyrifos, carbaryl) at laboratory conditions, in order to standardize the analytical procedures and to highlight eventual interferences on enzyme activities. Chemical concentrations in the mussel soft tissues were analyzed by GC/MS-MS. Main results showed a significant induction of EROD activity when mussels were exposed to 100 ng/l of PCB mixture of Arochlor 1260 and dioxin-like CB 126, but this congener showed also a clear competitive inhibition after 48 h of exposure. Surprisingly, pp'DDT determined a significant decrease of basal EROD activity after only 24 h of exposure, even if it was not possible to discriminate between the effect of the parent compound and that of its metabolites (DDD, DDE). We also found an interaction between the organophosphate insecticide chlorpyrifos, which does not directly decrease the AChE activity, and terbutilazine. This herbicide increased the biotransformation of the organophosphate compound to its oxidized metabolite (oxon), a much stronger AChE inhibitor. The possible use of the oxime Pyridine-2-Aldoxime Methochloride (2-PAM) to bring back the catalytic activity to basal levels was also demonstrated.

Quaternary and tertiary quinuclidine derivatives as inhibitors of choline uptake.

The uptake of choline into cholinergic neurons for acetylcholine (ACh) synthesis is by a specific, high-affinity, sodium- and temperature-dependent transport mechanism (HAChU). Of several quaternary quinuclidinol derivatives tested, the N-allyl derivative proved to be most potent. Though the methyl, ethyl, and isopropyl derivatives were less potent at comparable concentrations, at higher concentrations they also maximally inhibited HAChU. The benzyl, hydroxyethyl, and methoxyethyl derivatives failed to inhibit HAChU by greater than 50% at concentrations up to 100 microM. N-Allyl-3-quinuclidinol (NAQ) proved to be a specific inhibitor of HAChU (IC50 = 0.9 microM) and a poor inhibitor of both sodium-independent transport (IC50 = 680 microM) and choline acetyltransferase activity (Ki = 200 microM). The NAQ exhibited noncompetitive type inhibition compared with N-methyl-3-quinuclidinol, a competitive inhibitor of HAChU. Thus, substitution at the N-functional group not only alters potency, but may change the mechanism by which inhibition is produced. The optical isomers of NAQ and several derivatives were prepared and employed to examine the stereochemical selectivity for inhibition of choline uptake. The S(+)-isomer of NAQ (IC50 = 0.1 microM) had approximately 100-fold greater inhibitory activity for HAChU than the corresponding R(-)-isomer (IC50 = 10 microM). With all other quinuclidinols tested, the S(+)-isomers were also more potent than the corresponding R(-)-isomers. In an effort to obtain a tertiary inhibitor of HAChU that would be expected to cross the blood-brain barrier following peripheral administration, 3-biphenyl-3-quinuclidinol (BHQ) and 3-naphthyl-3-quinuclidinol (NHQ) were synthesized and evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)

Present status of POP contamination in Lake Maggiore (Italy).

In the last decade, Lake Maggiore has been subject to heavy DDT contamination due to a chemical plant located near the main influent of the Baveno Bay. The freshwater bivalve zebra mussel (D. polymorpha) was used as a bioindicator of several POPs (DDTs, PCBs, HCB, HCHs) to follow their concentration trend after a heavy flood in autumn 2000. Sampling of mollusc specimens were carried out monthly from April 2001 to October 2002 at two different stations in and outside the bay. Results showed worsening of DDT pollution due to the transport of insecticide from contaminated sediments and soils still present in the closed chemical plant site. Levels of about 4.5 microg/g lipids in soft tissues of specimens from the most contaminated site and 2.0 microg/g lipids outside it were found, which are twice those measured before the flood. HCHs and HCB values were always very low, but it was noticed since winter 2001-2002 a sharp increase of PCB pollution, with values of about 3-4 microg/g lipids, not due to the 2000 flood, but probably to improper discharge or release of contaminated sediments from numerous dams located in the watershed. Concentrations of total dioxin-like PCBs reached dangerous levels for the water community. Fish consumption may be a risk for human health especially for resident population, bearing in mind that fish usually have a higher POP concentration than zebra mussel.

A new kind of rehabilitation after Neer capsuloplasty: results.

The shoulder joint constitutes a sophisticated compromise between stability and movement: trauma such as dislocation and the surgery that follows to restore anatomical integrity, may cause a change in this balance, resulting in myofascial retraction, neuromotorial inhibition, and a deviation in motorial programming with the appearance of compensation. It is the purpose of this study to report the results obtained with a specific rehabilitation program in 18 patients submitted to Neer capsuloplasty to treat anterior shoulder instability. An objective and subjective study with pre-established stages, and a 12-month follow-up was done, to evaluate the results obtained based on the Rowe scale.

[Alzheimer's disease: factors affecting caregivers' workload]. / La malattia di Alzheimer: fattori che influenzano il carico di lavoro nel caregiver.

The aim of this study was to investigate which factors could play a role on the work-load of the Alzheimer patients' caregivers. The work-load was measured by means of Zarit's scale and inserted as dependent variable in a regression model, where the following independent variables were considered: education and MMSE of patients, age, sex of both patients and caregivers. The relevant factors resulted patient's age and MMSE, being significantly (p < 0.05) inversely associated with work-load. This score reached his maximum when patient's MMSE ranged between 14 and 16 (medium impairment). However, a large variability was found in this interval, suggesting a possible effect of other factors. In addition, we observed a decrement of work-load when patients were older, being higher at 50 and lower after 72. This effect might be explained by the significant change (especially in terms of social and familial life) due to the illness when the patient is relatively young. When the patient is older, Alzheimer' disease had smaller effect on the caregiver's work-load.

Mutation models for DVI analysis.

In recent years, the use of DNA data for personal identification has become a crucial feature for forensic applications such as disaster victim identification (DVI). Computational methods to cope with these kinds of problems must be designed to handle large scale events with a high number of victims, obtaining likelihood ratios and posterior odds with respect to different identification hypotheses. Trying to minimize identification error rates (i.e., false negatives and false positives), a number of computational methods, based either on the choice between alternative mutation models or on the adoption of a different strategy, are proposed and evaluated. Using simulation of DNA profiles, our goal is to suggest which is the most appropriate way to address likelihood ratio computation in DVI cases, especially to be able to efficiently deal with complicating issues such as mutations or null alleles, considering that data about these latter are limited and fragmentary.

Estimation of mutation probabilities for autosomal STR markers.

It is well known in forensic genetics that mutations on STR loci need not lead to genetic inconsistencies between the genotypes of parents and children (cf. [3,6,1]). In this article we look at a generalization of this phenomenon of "hidden" mutations: we investigate the probability with which a mutation of d repeat units appears to be one of k

Five to ten years follow-up after coiling of 241 patients with acutely ruptured aneurysms. A single centre experience.

Endovascular treatment has assumed a role of first choice in the management of ruptured intracranial aneurysms. We describe the clinical and morphological data after the treatment of 258 ruptured intracranial aneurysms in 241 patients, in order to evaluate the safety and the efficacy of the endovascular treatment. Two hundred and forty-one patients with saccular ruptured aneurysms were treated at our institution between 2000 and 2005. After the endovascular treatment a clinical and angiographic follow-up was conducted. The clinical follow-up was carried out with a medical examination and telephonic interviews and mRS was used for evaluation. Two hundred and forty-nine acutely ruptured aneurysms were successfully treated and immediately after the endovascular procedure 81.9% of the aneurysms resulted completely occluded, 12.1% had a residual neck and 6% revealed a residual sac. The evolution of each grade was evaluated at six months and two years. During the follow-up we observed five early and one late re-bleedings. Twenty-four patients underwent a second procedure. After the discharge and up to ten years 73.1% of patients had a good clinical outcome (mRS0-1), 8.9% died and the remainder showed moderate-severe disability (mRS2-3). The long-term stability of the anatomical result is a critic-al issue of this approach because eventual re-bleedings may occur even after several months or years. A careful clinical and radiological follow-up for up to two years after the embolization may prevent recurrences but may not be sufficient.

Enhanced vulnerability of PARK6 patient skin fibroblasts to apoptosis induced by proteasomal stress.

Proteasomal dysfunction and apoptosis are major hallmarks in the pathophysiology of Parkinson's disease (PD). PARK6 which is caused by mutations in the mitochondrial protein kinase PINK1 is a rare autosomal-recessively inherited disorder mimicking the clinical picture of PD. To investigate the cytoprotective physiological function of PINK1, we used primary fibroblasts from three patients homozygous for G309D-PINK1 as well as SHEP neuroblastoma cells stably overexpressing GFP-tagged wild type (wt) PINK1. Here we demonstrate that overexpression of wt PINK1 inhibits activation of Bax and release of cytochrome c, thereby diminishing caspase 9 processing and effector caspase activity after induction of proteasomal stress with the proteasome inhibitor (PI) MG132 in SHEP cells. Conversely, effector caspase activation induced by PIs, but not by the unrelated apoptotic stimulus staurosporine was potently enhanced in primary fibroblasts from homozygous PARK6 patients in comparison to those of heterozygous carriers or unaffected siblings. SHEP cells overexpressing wt PINK1 showed an elevated expression of the cytoprotective gene parkin, whereas PARK6 fibroblasts displayed significantly decreased expression of parkin in comparison to wild type control cells. Interestingly, overexpressed GFP-PINK1 was exclusively localized in the mitochondria of SHEP cells, but was redistributed to the cytoplasm under conditions of proteasomal stress. Our data indicate that PINK1 plays an important and specific physiological role in protecting cells from proteasomal stress, and suggest that PINK1 might exert its cytoprotective effects upstream of mitochondria engagement.

Integrated use of biomarkers and bioaccumulation data in Zebra mussel (Dreissena polymorpha) for site-specific quality assessment.

One of the useful biological tools for environmental management is the measurement of biomarkers whose changes are related to the exposure to chemicals or environmental stress. Since these responses might vary with different contaminants or depending on the pollutant concentration reached in the organism, the support of bioaccumulation data is needed to prevent false conclusions. In this study, several persistent organic pollutants -- 23 polychlorinated biphenyl (PCB) congeners, 11 polycyclic aromatic hydrocarbons (PAHs), six dichlorodiphenyltricholroethane (DDT) relatives, hexachlorobenzene (HCB), chlorpyrifos and its oxidized metabolite -- and some herbicides (lindane and the isomers alpha, beta, delta; terbutilazine; alachlor; metolachlor) were measured in the soft tissues of the freshwater mollusc Zebra mussel (Dreissena polymorpha) from 25 sampling sites in the Italian portions of the sub-alpine great lakes along with the measure of ethoxyresorufin dealkylation (EROD) and acetylcholinesterase (AChE) activity. The linkage between bioaccumulation and biomarker data allowed us to create site-specific environmental quality indexes towards man-made chemicals. This classification highlighted three different degrees of xenobiotic contamination of the Italian sub-alpine great lakes: a high water quality in Lake Lugano with negligible pollutant levels and no effects on enzyme activities, an homogeneous poor quality for Lakes Garda, Iseo and Como, and the presence of some xenobiotic point-sources in Lake Maggiore, whose ecological status could be jeopardized, also due to the heavy DDT contamination revealed since 1996.

Psychoendocrine investigation in schizophrenia: relationship between pituitary-gonadal function and behavior.

The Authors examine possible connections between the schizophrenic syndrome and the hypothalamo-pituitary-gonadal system, assuming that hormonal impairments may correlate with the appearance and development of peculiar behavioral features. The hormonal status and the behavioral parameters have been examined before, during and after a psychopharmacological therapy, and a combination of a psychopharmacological-hormonal treatment. Data have been obtained in 12 male hebephrenic schizophrenics, aged 18-36 years, with onset of the disease between 12 months and 20 years before our experiments. The patients were treated for 30 days with Haloperidol (6 mg.i.m.p.d. to a total dose of 180 mg.) and then for 45 days with Haloperidol at the same dose in combination with Chorionic Gonadotrophin (5000 I.U.i.m. twice a week for a total dose of 60.000 I.U.). The following hormonal assays were performed: total urinary gonadotrophins, serum FSH and LH, total urinary 17 ketosteroids, total urinary estrogens, serum testosterone. The hormonal assays were performed twice prior to therapy, twice during the Haloperidol therapy (12th and 26th days) twice during the Haloperidol plus HCG therapy (20th and 40th day) and 1 month after the withdrawal of the therapy. The psychological-behavioral parameters were examined through the Wittenborn Rating Scale. The result obtained seem to reveal a stimulatory effect of the Haloperidol plus HCG therapy on the deficient hormonal status. Moreover, it is evident that a constant correlation exists between biochemical improvement and behavioral improvement, especially in regard to affectivity disorders, adjustment to reality, active behavior.

Inhibition of high-affinity choline uptake and acetylcholine synthesis by quinuclidinyl and hemicholinium derivatives.

Choline uptake into cholinergic neurons for acetylcholine (ACh) synthesis is by a specific, high-affinity, sodium- and temperature-dependent transport mechanism (HAChU). To assess the role of choline availability in regulation of ACh synthesis, the structure-activity relationships of several hemicholinium (HC) and quinuclidinyl analogs were evaluated in a dose response manner. As confirms previous studies, the HCs, e.g., HC-3, acetylsecohemicholinium, and HC-15 are potent inhibitors of HAChU, HC-3 being the most potent (I50 = 6.1 X 10(-8) M). In the present study, the most potent quinuclidinyl derivative was the N-methyl-3-quinuclidinone (I50 = 5.6 X 10(-7) M). This compound had approximately 100-fold greater inhibitory activity than the corresponding racemic alcohol, suggesting that the 3-hydroxyl functional group is not absolutely essential for activity. Increasing the size of the N-functional group from a methyl to an allyl in the alcohol led to a 10-fold increase in activity. However, removal of the quaternizing N-methyl group yielding the tertiary amine, 3-quinuclidinol hydrochloride, greatly reduced its capacity to inhibit HAChU. Of the 2-benzylidene-3-quinuclidinone derivatives studied, only the m-chloro derivative significantly reduced HAChU.