Clinical and dopaminergic imaging characteristics of the FARPRESTO cohort of trial-ready idiopathic rapid eye movement sleep behavior patients

Introduction

Idiopathic/isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is considered the prodromal stage of alpha-synucleinopathies. Thus, iRBD patients are the ideal target for disease-modifying therapy. The risk FActoRs PREdictive of phenoconversion in iRBD Italian STudy (FARPRESTO) is an ongoing Italian database aimed at identifying risk factors of phenoconversion, and eventually to ease clinical trial enrollment of well-characterized subjects.

Methods

Polysomnography-confirmed iRBD patients were retrospectively and prospectively enrolled. Baseline harmonized clinical and nigrostriatal functioning data were collected at baseline. Nigrostriatal functioning was evaluated by dopamine transporter-single-photon emission computed tomography (DaT-SPECT) and categorized with visual semi-quantification. Longitudinal data were evaluated to assess phenoconversion. Cox regressions were applied to calculate hazard ratios.

Results

365 patients were enrolled, and 289 patients with follow-up (age 67.7 ± 7.3 years, 237 males, mean follow-up 40 ± 37 months) were included in this study. At follow-up, 97 iRBD patients (33.6%) phenoconverted to an overt synucleinopathy. Older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression, and visual semi-quantification of nigrostriatal functioning predicted phenoconversion. The remaining 268 patients are in follow-up within the FARPRESTO project.

Conclusions

Clinical data (older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression) predicted phenoconversion in this multicenter, longitudinal, observational study. A standardized visual approach for semi-quantification of DaT-SPECT is proposed as a practical risk factor for phenoconversion in iRBD patients. Of note, non-converted and newly diagnosed iRBD patients, who represent a trial-ready cohort for upcoming disease-modification trials, are currently being enrolled and followed in the FARPRESTO study. New data are expected to allow better risk characterization.     

Cabergoline influences ovarian stimulation in hyperprolactinaemic patients with polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterized by abnormal gonadotrophin secretion, in particular an elevated serum concentration of LH, depressed FSH, and an LH/FSH ratio of >or =2. Mild, transient hyperprolactinaemia is frequently associated with PCOS (30% of patients); furthermore, it can be observed during the late follicular and luteal phases of both natural and stimulated cycles. It is suggested that a reduction of the dopamine inhibitory effect might raise both prolactin (PRL) and LH. METHODS AND RESULTS: We compared ovarian stimulation in two groups of hyperprolactinaemic (hyperPRL)-PCOS patients; one group was treated with cabergoline, reducing PRL plasma concentrations to the range normally observed during ovulation induction. In the untreated hyperPRL-PCOS group, we noted a reduced total number of ampoules of recombinant FSH (P < 0.04), fewer days to reach HCG administration (P < 0.04), and significantly higher peak oestrogen plasma concentrations (P < 0.03) compared with the treated group. By ultrasound examination the same group showed significantly higher ovarian volume and an increased total number of follicles of every size. In untreated hyperPRL-PCOS patients, four cycles out of 65 were cancelled due to mild ovarian hyperstimulation syndrome (OHSS) that occurred during ovulation induction. Only one cycle out of 42 in the patients treated with cabergoline was cancelled. No significant differences in pregnancy rate nor in multiple pregnancy were found. CONCLUSION: Our data suggest a dopaminergic control of LH release and support the use of cabergoline in the management of such patients, in order to provide better clinical control of ovarian response and consequently a reduction of the risk of OHSS, with no decrease in pregnancy rate.     

Inhaled nitric oxide for pulmonary hypertension after heart transplantation.

BACKGROUND: Recipient pulmonary hypertension due to chronic congestive heart failure is a major cause of right ventricular (RV) dysfunction after heart transplantation. We hypothesized that inhaled nitric oxide (NO), in the postoperative period, would a) selectively reduce pulmonary vascular resistance and improve RV hemodynamics and b) reduce the incidence of RV dysfunction compared with a matched historical group. METHODS: Sixteen consecutive adult heart transplant recipients with lowest mean pulmonary artery (PA) pressures >25 mmHg were prospectively enrolled. Inhaled NO at 20 parts per million (ppm) was initiated before termination of cardiopulmonary bypass (CPB). At 6 and 12 hours after CPB, NO was stopped for 15 minutes and systemic and pulmonary hemodynamics were measured. RV dysfunction was defined as central venous pressure >15 mmHg and consistent echocardiographic findings. The incidence of RV dysfunction and 30-day survival in this group was compared with a historical cohort of 16 patients matched for pulmonary hypertension. RESULTS: Discontinuation of NO for 15 minutes at 6 hours after transplantation resulted in a significant rise in mean PA pressure, pulmonary vascular resistance (PVR), and RV stroke work index. Systemic hemodynamics were not affected by NO therapy. One patient in the NO-treated group, compared with 6 patients in the historical cohort group, developed RV dysfunction (P< .05). The 30-day survival in the NO-treated group and the historical cohort group were 100% and 81%, respectively (P> .05). CONCLUSION: In heart transplant recipients with pulmonary hypertension, inhaled NO in the postoperative period selectively reduces PVR and enhances RV stroke work. Furthermore, NO reduces the incidence of RV dysfunction in this group of patients when compared with a historical cohort matched for pulmonary hypertension. Inhaled NO is a useful adjunct to the postoperative treatment protocol of heart transplant patients with pulmonary hypertension.     

Reversible transdifferentiation of secretory epithelial cells into adipocytes in the mammary gland

Mammalian breast adipose tissue is replaced by a milk-secreting gland during pregnancy; the reverse process takes place upon interruption of lactation. Morphological and bromodeoxyuridine studies provide indirect evidence that mouse mammary adipocytes transform into secretory epithelial cells during pregnancy and revert to adipocytes after lactation. By using the Cre-loxP recombination system we show that the mammary gland of whey acidic protein (WAP)-Cre/R26R mice, in which secretory epithelial cells express the lacZ gene during pregnancy, contains labeled adipocytes during involution. Conversely, adipocyte P2-Cre/R26R mice, in which adipocytes are labeled before pregnancy, contain labeled secretory epithelial cells during pregnancy. We conclude that reversible adipocyte-to-epithelium and epithelium-to-adipocyte transdifferentiation occurs in the mammary gland of adult mice during pregnancy and lactation.     

Influence of growth hormone on the immunosuppressive effect of prednisolone in mice

Growth hormone can be used to counteract some catabolic effects of long-term administration of glucocorticoids, such as impairment of growth in children and osteoporosis. However, owing to its immunostimulatory properties the hormone may counteract the effect of glucocorticoids on the immune system. To investigate this question we administered different doses of hGH (4, 8, 40 IU/kg) to C57/Bl/6J mice treated for two days with prednisolone, and evaluated thymus and spleen parameters and natural killer activity. Growth hormone at the dose of 4 and 8 IU/kg reversed prednisolone-induced reduction of spleen and thymus weight and cellularity, whereas the highest dose showed to be immunosuppressive in itself. Two days after treatment withdrawal, a recovery of spleen parameters was evident, whereas the thymus was still suppressed by preceding prednisolone or hGH (40 IU/kg) treatments. The pattern of natural killer activity displayed by the splenocytes resembled that present under treatment. In a second experiment prednisolone, administered for 10 days, drastically reduced the number of viable spleen and thymus cells as well as the relative spleen and thymus weights, an effect reversed by concomitant administration of hGH (0.8, 4, 8 IU/kg). Natural killer activity, which was significantly depressed by prednisolone, was restored by the intermediate GH dose only. The 8 IU/kg GH dose was immunosuppressive in itself.     

Antioxidant drugs combined with alpha-interferon in chronic hepatitis C not responsive to alpha-interferon alone: a randomized, multicentre study

OBJECTIVE: After non-response to the initial course of therapy, retreatment with alpha-interferon is not effective. The aim of this study was to ascertain whether the administration of N-acetyl cysteine and vitamin E could increase the response rate to retreatment with alpha-interferon. DESIGN: Prospective, multicentre clinical trial. SETTING: Twelve hospitals in Lombardy, Italy. PARTICIPANTS: 120 consecutive patients affected by biopsy-proven chronic hepatitis C who had been non-responders to a previous course of alpha-interferon, administered at the dosage of 3-6 million units (MU) three times a week (tiw) for 6 months. INTERVENTIONS: The patients were randomly assigned to one of two groups of treatment: group A, natural interferon-alphaN3, 6 or 9 MU tiw, when the body weight was < 60 kg or > or = 60 kg, respectively; group B, the same dosage of natural interferon-alphaN3 in association with oral administration of N-acetyl cysteine 1200 mg/day and vitamin E 600 mg/day. The period of treatment was 6 months in both groups. RESULTS: Neither end-therapy biochemical response nor sustained biochemical response rates were improved by the combination treatment, and in no case was clearance of the virus from serum observed. CONCLUSIONS: In this randomized study carried out on 120 patients with chronic hepatitis C not responsive to alpha-interferon, oral supplementation with N-acetyl cysteine and vitamin E did not improve the poor efficacy of retreatment with alpha-interferon alone.     

Diabetic neuropathy in db/db mice develops independently of changes in ATPase and aldose reductase

Summary ATPase activity was investigated in sciatic and optic nerves of female mutant diabetic C57Bl/Ks (db/db) mice and age-matched control mice (db/m and m/m). Nerves from animals aged 50, 70, 125, 180 and 280 days were assayed in vitro for ATPase activity in the presence or absence of ouabain: the ouabain-sensitive fraction contained Na⁺,K⁺-ATPase. Enzymatic activity was compared within and between age-matched groups. No significant difference in Na⁺,K⁺-ATPase activity was detected between the diabetic and control mice, whether expressed as mol P_i/h^–1 formed per gramme wet weight or per nerve (protein content). The activity decreased by about 25% in both the sciatic and optic nerves of the oldest animals. These results were strikingly similar in all groups, regardless of the type of nerve examined, confirming that the development of neuropathy in this animal model is unrelated to the postulated derangement of Na⁺,K⁺-ATPase activity. Among possible explanations, a lack of polyol pathway activation was investigated by staining the sciatic nerves of animals from all groups with the peroxidase-antiperoxidase procedure using a polyclonal antiserum raised against the enzyme aldose reductase. Histological sections of all nerves were consistently negative, suggesting that these animals actually lack the enzyme involved in activating the self-perpetuating metabolic cycle leading to deranged nerve function. The db/db mouse appears to present particular biochemical changes which merit attention with a view to clarifying the pathogenesis of diabetic neuropathy.