Effects of acute and chronic treatment with fluvoxamine on extracellular and platelet serotonin in the blood of major depressive patients. Relationship to clinical improvement.

The effects of the treatment with fluvoxamine (FVX) on platelet and plasma serotonin (5-HT) have been examined in eleven drug-free major depressive patients. Acute FVX was without effect, whereas the repeated oral treatment (100-150 mg daily, 12 weeks) reduced platelet 5-HT (-89%, P less than 0.001) and plasma 5-HT (-60%, P less than 0.02). Patients who responded to the treatment at 6 weeks (Hamilton score less than or equal to 10) had significantly lower (-39%, P less than 0.02) pretreatment values of platelet 5-HT than the rest. This suggests that 'low 5-HT' patients may have a more rapid improvement after fluvoxamine. Platelet 5-HT and HDRS correlated significantly along the treatment (r = 0.679, P less than 0.01). These data demonstrate a marked action of fluvoxamine as 5-HT uptake inhibitor at therapeutic doses and confirm that this mechanism is relevant for its efficacy as antidepressant drug.     

Identification of 26 new constitutional RB1 gene mutations in Spanish, Colombian, and Cuban retinoblastoma patients

Constitutional mutations in the RB1 gene predispose to retinoblastoma development. Hence genetic screening of retinoblastoma patients and relatives is important for genetic counseling purposes. In addition, RB1 gene mutation studies may help decipher the molecular mechanisms leading to tumors with different degrees of penetrance or expressivity. In the course of genetically screening of 107 hereditary and non-hereditary retinoblastoma patients (11 familiar bilateral, 4 familiar unilateral, 49 sporadic bilateral and 43 sporadic unilateral) and kindred from Spain, Colombia and Cuba, using direct PCR sequencing, we observed 45 distinct mutations and four RB1 deletions in 53 patients (9 familiar bilateral, 2 familiar unilateral, 31 sporadic bilateral and 11 sporadic unilateral). Most of these mutations (26/45, 57%) have not been reported before. In 32 patients, the predisposing mutations correspond to nonsense (mainly CpG transitions) and small insertions or deletions whose expected outcome is a truncated Rb protein that lacks the functional pockets and tail. Five single aminoacid replacements and seventeen mutations affecting splicing sites were also observed in retinoblastoma patients. Two of these sixteen mutations are of unclear pathogenic nature.     

A possible paracellular route for the resolution of hydrocephalic edema

Summary Considering the possibility of a paracellular route for edema resolution we studied the microvasculature of the subependymal and subcortical white matter in hydrocephalic rats. Normal adult rats were used as controls. After injection of kaolin suspension into the cisterna magna, the animals were killed at intervals of 1, 2, 4, and 8 weeks. In hydrocephalic rats at 1 week after kaolin injection, widening of the interendothelical cleft between the tight junction (dehiscence) was seen in 27 of 76 (35%) vessels. At 2 weeks after kaolin injection, the number of the dehiscences had increased (39/7:56%) and some were enlarged, forming interendothelial blisters. At 4 weeks in hydrocephalic rats, both dehiscences and blisters were still prominent (45/7363%) and at 8 weeks the dehiscences were still prominent, but the number of the blisters had decreased (25/8131%). The blisters and dehiscences were most pronounced in the corpus callosum and occipital regions. Following i.v. injection of horseradish peroxidase, the interendothelial dehiscences and blisters were completely devoid of the marker substance. These findings indicate that in obstructive hydrocephalus the tight junctions may constitute part of a paracellular pathway for the resorption of interstitial edema fluid.     

Control of 5-hydroxytryptamine release in the dorsal raphe nucleus by the noradrenergic system in rat brain. Role of alpha-adrenoceptors.

The interactions between the brainstem serotonergic (5-hydroxytryptamine, 5-HT) and noradrenergic (NA) systems are important for the pathophysiology and treatment of affective disorders. We examined the influence of alpha-adrenoceptors on 5-HT and NA release in the rat dorsal raphe nucleus (DR) using microdialysis. 5-HT and NA concentrations in DR dialysates were virtually suppressed by TTX and increased by veratridine. The local and systemic administration of the alpha(1)-adrenoceptor antagonist prazosin reduced the DR 5-HT output but not that of NA. The maximal 5-HT reduction induced by local prazosin administration (-78% at 100 microM) was more marked than by its systemic administration (-43% at 0.3 mg/kg). The local application of NA and desipramine, to increase the tone on DR alpha(1)-adrenoceptors, did not enhance 5-HT release. The local (100 microM) or systemic (0.1-1 mg/kg s.c.) administration of clonidine reduced 5-HT and NA release (-48 and -79%, respectively, at 1 mg/kg), an effect reversed by RX-821002, which by itself increased both amines when given systemically. DSP-4 pretreatment prevented the effects of clonidine on 5-HT, suggesting the participation of alpha(2)-adrenoceptors on NA elements. Moreover, the systemic effect of clonidine on 5-HT (but not NA) was cancelled by lesion of the lateral habenula and by anesthesia, and was slightly enhanced by cortical transection. These data support the view that alpha(1)-adrenoceptors in the DR tonically stimulate 5-HT release, possibly at nearly maximal tone. Likewise, the 5-HT release is modulated by alpha(2)-adrenoceptors in NA neurons and in forebrain areas involved in the distal control of 5-HT neurons.     

Modulation of serotonergic function in rat brain by VN2222, a serotonin reuptake inhibitor and 5-HT1A receptor agonist.

VN2222 (1-(benzo[b]thiophen-3-yl)-3-[4-(2-methoxiphenyl piperazin-1-yl]propan-1-ol) is a potential antidepressant with high affinity for the serotonin transporter and 5-HT(1A) receptors. Locally applied, VN2222 enhanced the extracellular 5-hydroxytryptamine (5-HT) concentration (5-HT(ext)) in rat striatum to 780% of baseline whereas its systemic administration (1-10 mg/kg s.c.) reduced 5-HT(ext). In the presence of citalopram, 8-OH-DPAT or VN2222 applied in medial prefrontal cortex reduced 5-HT(ext). Fluoxetine, VN2222, and 8-OH-DPAT suppressed the firing rate of dorsal raphe 5-HT neurons (ED(50): 790, 14.9, and 0.8 microg/kg i.v., respectively). These effects were antagonized by WAY 100635. Administration of VN2222 for 2 weeks desensitized 5-HT(1A) receptors as assessed by microdialysis and single-unit recordings (ED(50) values for 8-OH-DPAT were 0.45 and 2.34 microg/kg i.v. for controls and rats treated with 6 mg/kg day VN2222). These results show that VN2222 is a mixed 5-HT reuptake inhibitor/5-HT(1A) agonist that markedly desensitizes 5-HT(1A) autoreceptors. These properties suggest that it may be a clinically effective dual action antidepressant drug.     

Complications of laparoscopic splenectomy

HYPOTHESIS: Analysis of the type and characteristics of complications after laparoscopic splenectomy may permit the identification of clinical factors with predictive value for the development of complications. DESIGN: Univariate and multivariate analysis of factors related to complications in a prospective series of laparoscopic splenectomies. SETTING: A large tertiary referral university-teaching general hospital. PATIENTS: One hundred twenty-two nonselected consecutive patients, in whom laparoscopic splenectomy was attempted between February 1993 and July 1999. INTERVENTION: Laparoscopic splenectomy. MAIN OUTCOME MEASURES: Immediate complications classified according to the Clavien score. Univariate and multivariate analyses were performed of complications related to age, sex, body mass index, and malignant nature of the hematologic disease; preoperative hematocrit and platelet count; operative time; operative position; need of accessory incision; transfusion status; learning curve; and existence of comorbid diseases. RESULTS: One hundred thirteen laparoscopic splenectomies were completed (conversion rate, 7.4%). Twenty patients (18%) developed 23 complications. All were Clavien type I or II, without mortality. One complication was intraoperative (diaphragmatic perforation), and 22 were postoperative: 6 pulmonary (26%), 3 fever (13%), 8 hemorrhagic (35%) (5 episodes of postoperative bleeding and 3 abdominal wall hematomas), and 6 others (26%). Ten (43%) of the 23 were technically related. Univariate analysis showed that complications were only related to age (mean +/- SD, 55 +/- 15 vs 39 +/- 17 years; P<.008) or transfusion (50% vs 11%; P<.001). Multivariate analysis showed that the learning curve (P<.005; 95% confidence interval, 2.46), age (P<.001; 95% confidence interval, 1. 04), spleen weight (P<.009; 95% confidence interval, 1.00), and malignant neoplasm diagnosis (P<.007; 95% confidence interval, 3.82) were independent predictors of complications. CONCLUSIONS: Laparoscopic splenectomy is feasible, and the incidence of severe complications is reduced. However, a high proportion of these complications are technique related. Laparoscopic splenectomy requires great technical care but offers major clinical advantages, even in less favorable situations, such as in patients with splenomegaly or with malignant neoplasms.     

The cerebrospinal fluid/serum leptin ratio during pharmacological therapy for obesity

The aim of the present study was to evaluate the cerebrospinal fluid (CSF)/serum leptin ratio during pharmacological therapy for obesity with centrally and peripherally acting drugs. Thirty-one obese women (mean age, 32.3 +/- 10 yr; body mass index, 38.2 +/- 5.2 kg/m(2); body fat, 43.3 +/- 5.4%) were studied before and 2 months after a weight loss program consisting of a balanced diet (1200 kcal/d) plus drug therapy. The patients were randomly assigned into three study groups: group I, fenproporex 25 mg/d (n = 10); group II, sibutramine 10 mg/d (n = 10); and group III, orlistat 120 mg tid (n = 11). Body fat, measured by dual-energy x-ray absorptiometry, and serum and CSF concentrations of leptin were examined at baseline and 2 months after therapy. At baseline, clinical and biochemical characteristics of the groups were similar. All of the women lost weight, approximately 7.0% of their initial body weight, and the reduction was not different among the groups. Serum leptin fell significantly after 2 months in all groups, and the decline was proportional to the reduction in body fat, because leptin levels adjusted for body fat did not change after treatment. CSF leptin levels showed a significant decrease after 2 months in all groups, and this decline was higher on group III compared with group I (P = 0.006). After therapy, the CSF/serum leptin ratio did not change in group I (1.57 +/- 0.3 to 1.72 +/- 0.62%) and group II (1.78 +/- 1.01 to 1.69 +/- 1.27%), whereas it declined significantly in group III (1.65 +/- 0.43 to 1.09 +/- 0.47%; P < 0.01), corresponding to a decrease of 33.3 +/- 22.5% for the CSF/serum leptin ratio. The percentage change in group III was significantly different from the positive variation on group I (11.9 +/- 42.1%; P = 0.006) and close to the statistical significance compared with the negative variation seen in group II (-7.6 +/- 27.8%; P = 0.06). Our results showed that the CSF/serum leptin ratio decreased after weight loss in obese women treated during 2 months with orlistat, whereas this ratio did not change in this period of time in obese women treated with fenproporex and sibutramine.