Metabolic fate of zetidoline,a new neuroleptic agent,in man

Summary Healthy volunteers administered orally a single dose (20 mg) of [2-¹⁴C]zetidoline, a new dopamine antagonist, exhibited rapid absorption of radioactivity with peak plasma levels of 250–300 ng/ml achieved in 1 h. The compound underwent intensive metabolic first-pass so that plasma radioactivity was represented mostly by two products, metabolite B endowed with neuroleptic activity, and metabolite D inactive, while unchanged zetidoline was not detected. Disappearance of radioactivity from plasma was rapid with a half-life of 1.78±0.20 h.The simultaneous assay of plasma prolactin showed increased levels of the hormone (+464% at the peak time) up to the 6th h after dosing, with plasma concentration profile which mimic those of metabolite B.The radioactive test-dose was eliminated mainly via the kidneys with an average urinary recovery of 84.7±1.7% in 4 days (73.4±1.1% within 8 h). The main urinary metabolite (metabolite G) and two minor ones (metabolites B and D) were purified and their structures assigned by IR, MS and NMR spectroscopy, they are: 1-(3-chloro-4-hydroxyphenyl)-3[2-(3,3-dimethyl-1-azetidinyl)ethyl]imidazolidin-2-one, metabolite B; 1-[2-(3,3-dimethyl-1-azetidinyl)ethyl]imidazolidin-2-one, metabolite D and the 4-O-sulphate ester of metabolite B, metabolite G.The metabolic fate of zetidoline in man follows the same phase I reactions demonstrated in rats and dogs, while the phase II reaction is sulphoconjugation instead of the glucuronidation observed in animals.     

Normal sperm parameters per se do not reliably account for fertility: A case–control study in the real-life setting

A proportion of men are infertile despite having normal medical history/physical examination and normal semen analysis. We aimed to assess whether normal sperm parameters per se account for male factor fertility. 1,957 infertile men were compared with 103 age-comparable fertile controls. Semen analysis was based on 2010 World Health Organization reference criteria. Of all, 12.1% of infertile men and 40.8% of fertile men presented with normal sperm parameters. Among fertile men, 36.9% had isolated sperm abnormalities and 22.3% men showed two or more concomitant sperm abnormalities. Serum total testosterone was higher in infertile men with normal sperm parameters compared to those with ≥2 sperm abnormalities or azoospermia, but similar to those with isolated sperm abnormalities (p ≤ .001). Circulating hormones were similar among sperm parameters groups in fertile men. At multivariable analyses, testicular volume (OR 1.12, p ≤ .001) and FSH (OR 0.8, p ≤ .001) were associated with normal sperm parameters. Overall, the longer the infertility period, the greater the number of sperm parameters abnormalities (p < .01). In conclusion, we found that 12% of infertile men and only 41% of fertile men present with normal sperm parameters. Normal sperm parameters per se do not reliably account for fertility in the real-life setting.     

Giant cell arteritis presenting as a stroke in the internal carotid artery territory: a case-based review

Giant cell arteritis (GCA) is a large-vessel vasculitis, typically affecting the aorta and its branches. The involvement of vertebral and internal carotid arteries occurs in a limited number of cases, and stroke as a presenting symptom of GCA is extremely unusual: this subset of the disease has a poor prognosis and rarely responds to immunosuppression.We report the case of a 70-year-old woman, who presented to the Emergency Department for ischemic stroke, which appeared to be the first and only symptom of GCA. The prompt administration of steroids and tocilizumab (TCZ) led to clinical and radiological resolution, with no residual disability at 6-month follow-up.Our case-based review, highlighting the rarity of a large vessel vasculitis presenting only with a cerebrovascular accident, provides new evidence for the efficacy of TCZ even in more unusual varieties of GCA: in these cases, TCZ should be immediately prescribed, in order to prevent mortality and severe long-term morbidity.     

Primary Hepatic Lymphoma After Lung Transplantation: A Report of 2 Cases

BackgroundDiffuse large B-cell lymphoma (DLBCL) is the most common subtype of non–Hodgkin lymphoma in the posttransplant setting. Treatment is based on chemotherapy; surgery is still debated and should be performed in very select cases.MethodsWe observed 2 patients out of 300 who underwent lung transplantation in the Nouvel Hopital Civil between 2013 and 2019 with primary hepatic lymphoma. Chemotherapy with a rituximab-cyclophosphamide, hydroxydaunorubicin, vincristine, prednisone protocol was performed in all patients. Mycophenolate mofetil was interrupted before treatment, and everolimus was introduced after chemotherapy by associating tacrolimus withdrawal.ResultsOne patient showed complete remission; after 7 years, no recurrence has been noticed. The second is still undergoing chemotherapy with no signs of disease progression.ConclusionsDLBCL risk is higher in solid organ transplant recipients than in the general population. Primary hepatic lymphoma diagnosis is often difficult and based on histologic findings after initial clinical and radiological suspicion of primary or secondary liver neoplasia. Diagnosis is challenging because no clinical, radiological, or biological features exist. Biopsy is always indicated for histologic confirmation. Chemotherapy is the mainstay of therapy, but surgery may be indicated in very select patients.     

Mental health services and the city: a neighbourhood-level epidemiological study

Journal of Public Health - Neighbourhood composition is considered a social determinant of mental health that can be addressed by policymakers to improve outcomes. Deprived neighbourhoods typically...     

Prognostic Stratification by Conventional Echocardiography of Patients with Aortic Stenosis: The “CAIMAN‐ECHO Score”

Background and Aim: Surgery is not recommended in asymptomatic patients with aortic stenosis (AS). However, prognosis of these patients is worse than retained. We built a simple score (named by the acronym “CAIMAN”) for stratifying asymptomatic patients with AS according to the different risk for cardiovascular events. Material and Methods: Data from 141 patients with moderate‐to‐severe AS followed up for 36 months were analyzed. The end point “outcome” was defined as death of all causes or aortic valve replacement imposed by symptoms or hospital admission for myocardial infarction and/or heart failure. The score was validated in 143 patients prospectively recruited in 2 different centers. Results: The 40 events occurred in the original cohort were associated with higher aortic transvalvular peak jet velocity, calcium score, and observed/predicted left ventricular (LV) mass ratio. Based on the hazard ratios of Cox analysis, the score was calculated as follows: calcium score 1–3 = 1 point, 4 = 6 points; transvalvular peak jet velocity ≤3.6 m/sec = 1 point, 3.6 m/sec = 3 points, observed/predicted LV mass ratio ≤110% = 1 point, >110% = 3 points. After a mean period of 28 ± 18 months, event‐free survival was 18%, 42%, 91%, and 96% in the 4 quartiles of echo score. The accuracy of the score in predicting events was 84% and 77% (P = 0.09) in the original and validation cohort, respectively. Conclusions: The CAIMAN‐ECHO score is a simple and feasible tool useful for an accurate prognostic stratification of patients with asymptomatic moderate‐to‐severe AS.