A genetic determinant of the striatal dopamine response to alcohol in men.

Excessive alcohol use, a major cause of morbidity and mortality, is less well understood than other addictive disorders. Dopamine release in ventral striatum is a common element of drug reward, but alcohol has an unusually complex pharmacology, and humans vary greatly in their alcohol responses. This variation is related to genetic susceptibility for alcoholism, which contributes more than half of alcoholism risk. Here, we report that a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and [(11)C]-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. To directly establish the causal role of OPRM1 A118G variation, we generated two humanized mouse lines, carrying the respective human sequence variant. Brain microdialysis showed a fourfold greater peak dopamine response to an alcohol challenge in h/mOPRM1-118GG than in h/mOPRM1-118AA mice. OPRM1 A118G variation is a genetic determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward.

Multiple G-protein betagamma combinations produce voltage-dependent inhibition of N-type calcium channels in rat superior cervical ganglion neurons.

Activation of several G-protein-coupled receptors leads to voltage-dependent (VD) inhibition of N- and P/Q-type Ca(2+) channels via G-protein betagamma subunits (Gbetagamma). The purpose of the present study was to determine the ability of different Gbetagamma combinations to produce VD inhibition of N-type Ca(2+) channels in rat superior cervical ganglion neurons. Various Gbetagamma combinations were heterologously overexpressed by intranuclear microinjection of cDNA and tonic VD Ca(2+) channel inhibition evaluated using the whole-cell voltage-clamp technique. Overexpression of Gbeta1-Gbeta5, in combination with several different Ggamma subunits, resulted in tonic VD Ca(2+) channel inhibition. Robust Ca(2+) channel modulation required coexpression of both Gbeta and Ggamma. Expression of either subunit alone produced minimal effects. To substantiate the apparent lack of Gbetagamma specificity, we examined whether heterologously expressed Gbetagamma displaced native Gbetagamma from heterotrimeric complexes. To this end, mutant Gbeta subunits were constructed that differentially modulated N-type Ca(2+) and G-protein-gated inward rectifier K(+) channels. Results from these studies indicated that significant displacement does not occur, and thus the observed Gbetagamma modulation can be attributed directly to the heterologously expressed Gbetagamma combinations.

Dihydropyridine-sensitive Ca2+ influx modulated by stretch in A7r5 vascular smooth muscle cells.

We examined 45Ca2+ influx in A7r5 vascular smooth muscle cells under cyclical stretch and static conditions and compared the results obtained at resting membrane potential (2.5 mM [K+]o, Em = -58 mV according to uptake of [3H]tetraphenylphosphonium) with those under depolarizing conditions (70 mM [K+]o, Em = -27 mV). Application of 10% average strain (24% maximum) in cycles of 3 s on, 3 s off at resting Em caused a 5-fold increase in Ca2+ influx rate to a level similar to depolarized cells and depolarized, stretched cells. 1 mu M (+)-isradipine blocked 90% of the stretch- or depolarization-activated Ca2+ uptake. When the cells were stretched under Na+ -free conditions, a reduction, not activation, of Ca2+ influx rate occurred. Our results suggest that stretching of cultured aortic vascular smooth muscle cells enhances Ca2+ uptake through a voltage-dependent, dihydropyridine-sensitive Ca2+ entry pathway, whose activation by stretch is dependent upon extracellular Na+.

Modulation of dihydropyridine receptors in vascular smooth muscle cells by membrane potential and cell proliferation.

We have studied binding of isradipine to A7r5 vascular smooth muscle cells as a function of membrane potential and cell proliferation. Consistent with a voltage-modulated receptor model, two classes of binding sites were detected in confluent cultures: high-affinity sites under depolarizing (50 mM K+) conditions (Kd = 45 +/- 3 pM), and lower affinity sites under resting (5 mM K+) conditions (Kd = 181 +/- 20 pM). However, proliferating cells also displayed the high-affinity state at rest (Kd = 29 +/- 9 pM) in addition to a low-affinity site (Kd = 869 +/- 383 pM). Analysis of dissociation rates also revealed two receptor classes during proliferation. Proliferating cells showed a single class of high-affinity sites (Kd = 39 +/- 6 pM) when depolarized, similar to confluent cells. Receptor density in confluent monolayers increased from 15 +/- 3 fmol/10(6) cells at 5 days to 72 +/- 6 fmol/10(6) cells after 10 days. These results suggest (i) that some L-type Ca2+ channels are spontaneously active in proliferating vascular smooth muscle cells, but require depolarization to activate in a confluent monolayer, and (ii) that the density of dihydropyridine receptors increases after a monolayer becomes confluent.

Pregnancy in hyperprolactinemic women.

Pregnancy achieved in women who receive treatment to correct the secretory dysfunction of nontumoral HPRL or microprolactinomas requires close prenatal care, but generally its course does not vary from normal. When a macroprolactinoma is present, consequences of pregnancy are insignificant, provided the tumor has been previously treated or bromocriptine is given continuously during the pregnancy. On those rare occasions when symptoms of tumor growth appear during pregnancy, bromocriptine and dexamethasone effectively control such manifestations. Breast-feeding of the infant can be allowed, and a second pregnancy within a short term is not contraindicated. When a new pregnancy is not desired, nonhormonal contraceptive methods are advised. Patients with nontumoral HPRL and microadenomas require periodic checkups. Macroadenomas may be surgically excised, but longterm bromocriptine treatment also achieves good results and is highly recommended.

Endometrial pathology and infertility.

OBJECTIVE: To call attention to endometrial pathologies, which in addition to causing menstrual problems, are a cause of infertility. DESIGN: Controlled clinical study. SETTING: Specialized unit in the management of infertile patients. PATIENT(S): Fifteen infertile women between the ages of 26 and 39 years and suffering infertility from endometrial problems for a period of 4 to 18 years were included in the study. Six patients had primary infertility and nine others had secondary infertility. INTERVENTION(S): Once the endometrial pathology was diagnosed, treatment was initiated according to the type of problem: hysteroscopy, curettage, and hormonal replacement with or without corticoids or antiphymic drugs. MAIN OUTCOME MEASURE(S): Clinical studies, laboratory tests, hormonal serum levels, and endoscopy. RESULT(S): After initiating specific treatment for each of the pathologies, menstruation was re-established in 14 of 15 patients. Nine patients became pregnant (8 of 10 cases with bone, squamous cell, or muscular metaplasia). CONCLUSION(S): Pathological changes of the endometrium are causes of infertility. These problems are not as rare as thought. They must be searched for carefully and diagnosed promptly. The majority carry a good prognosis when adequately treated.

Ethynodiol diacetate as a contraceptive.

PIP: 437 multiparous women were given ethynodiol diacetate in continuous microdoses of .35 mg/day, .50 mg/day, .25 mg/twice a day, or .125 mg/twi ce a day. 7 pregnancies occurred during treatment, 5 due to medication failure; 2 were in the .5 mg/day group and 3 were in the .125 mg/twice a day group. Women taking .5 mg/day and .25 mg/twice a day had most menstrual irregularities (10% of the cycles). Side effects noted were: headache, nervousness, nausea and vomiting, and abdominal pain. Most of the patients lost weight; lactation did not appear to be affected by the medication. Uterine tone changed during treatment; there was a decrease in frequency, an increase in intensity and an increase in the tone of the contractions. It is concluded that the contraceptive efficacy was directly related to dosage as were menstrual and uterin disturbances, except for side effects. Ovulation was not inhibited although contraception was produced.^ieng

Heterologous expression of a green fluorescent protein-pertussis toxin S1 subunit fusion construct disrupts calcium channel modulation in rat superior cervical ganglion neurons.

The fusion construct pEGFP-PTXS1 was assembled by ligating cDNA encoding the S1 subunit of Bordetella pertussis toxin (PTX) into the plasmid pEGFP-C1 (which codes for enhanced green fluorescent protein). Microinjection of pEGFP-PTXS1 (1-100 ng/microl) into the nucleus of dissociated rat sympathetic ganglion neurons resulted in functional expression as determined from the diffuse green fluorescence and disruption of norepinephrine-mediated N-type Ca2+ channel modulation. The heterologously expressed toxin retained specificity for G alpha(i/o)-dependent pathways as VIP-mediated modulation of N-type Ca2+ channels and muscarine-mediated inhibition of M-type K+ channels persisted in pEGFP-PTXS1 expressing neurons. These data demonstrate that the S1 subunit of PTX is readily expressed in mammalian neurons and remains functional following fusion to the C-terminus of another protein.

Hyperprolactinemia and mammary prostheses. A report of eight cases.

Eight young women developed clinical manifestations of hyperprolactinemia after the application of bilateral methylpolixolosane mammary prostheses. Elevated serum levels of prolactin were present in all cases. Treatment with bromocriptine or methergoline corrected the excessive prolactin production and associated symptoms. The pathophysiology of this syndrome is unexplained as yet.

Goserelin followed by assisted reproduction: results in infertile women with endometriosis.

OBJECTIVE: Demonstrate the usefulness of combined treatment of a Gn-RH agonist and assisted reproduction in the management of infertile women with endometriosis. DESIGN: A prospective evaluation of goserelin's action (Gn-RH(a)) in the extension of endometriosis, of its suppression and clinical improvement, and in pregnancy rates after an immediate assisted reproduction program. SITE: Infertility clinic at a private hospital related to other university hospitals. PATIENTS: 18 infertile patients with laparoscopically-confirmed endometriosis. METHOD: All women were submitted to general laboratory tests, FSH, LH and estradiol measurements, and laparoscopy before and after treatment. All were treated for 6 months with goserelin and, when menstruating, the patients were submitted to an assisted reproduction program with a scheme of HMG + FSH + HCG. MAIN OUTCOME MEASURES: Improvement of endometriosis and achievement of pregnancy. RESULTS: An improvement of the endometriosis score was confirmed in 100% of the cases. The average pretreatment score of 44.8 points decreased to 18.3 after treatment. Similarly, the pain reported by eight of the patients practically disappeared after using the Gn-RH analogue. During treatment with goserelin, all women had amenorrhea. Their periods resumed in an average of 80.5 days after the last injection. In three (17.6%) cases, no follicular response was obtained, and stimulation was suspended. The remaining responses were good: eight GIFT procedures, four IVF-ET procedures and two IUIs resulted in eight pregnancies (57.1%), one of which terminated in an abortion (the patient became pregnant again). The eight pregnancies had good results: one was double and another quadruple. Most importantly, all pregnancies were achieved during the first treatment attempt. CONCLUSION: Combined treatment of goserelin with immediate assisted reproduction is a satisfactory procedure, which achieves a high percentage of pregnancies at the first try and with few abortions in cases of infertile women with endometriosis.

[Effect of prostaglandin F2a on the contractility of the pregnant human uterus]. / Efecto de la prostaglandina F2a sobre la contractilidad del útero humano grávido

PIP: (PGF2alpha) Prostaglandin F2alpha was administered intraamniotically to 16 patients in 3 groups: molar pregnancy (8 cases), fetal death (6 cases), and anencephalic fetus (2 cases). These particular types of situations were selected because the effects of PGs upon the product were unknown. PG was administered in dosages between 3 and 200 mcg after being prepared in an ethanol solution. It appeared to have no effect on uterine contractility. It is best to start contractility stimulation with low doses which should be increased progressively according to uterine response. Tone, intensity, frequency, and uterine activity increased when PG dose was increased. Uterine labor as to maturity and cervical dilatation, was studied in the 3 groups. Blood pressure was registered in 2 patients with molar pregnancy; there were no changes during the 1st hours of the study. However, during the last part, differential pressure increased by systolic increase. In 4 patients with fetal death, cervical dilatation register was taken. Average dilatation time (going from 2-10 cm) was 9.50 hours. There were such side effects as slight nausea, vomiting, and chills. 1 of the patients presented with hypotension upon administration of PGF2alpha 200 mcg. 4 patients suffered complications; 1 with molar pregnancy had a possible pulmonary embolism by trophoblast, another had hemorrhage and hypotension, 1 patient with fetal death had immediate hypotension after administration of 200 mcg, and the other had deciduo-myometritis which cleared with antibiotics and curettage. No other subjects experienced complications. Intraamniotic PG administration produced few side effects. (author's modified)^ieng

[Post-cesarean ovarian transposition as a method of reversible sterilization: initial study]. / Transposición ovárica postcesárea como método de esterilización reversible: estudio inicial.

PIP: A reversible method of sterilization to be performed during cesarean section by moving the ovary through the mesosalpinx to the front of the tube is described. 22 patients at a Mexican Institute of Social Security Hospital who did not wish further pregnancies but did not want definitive sterilizations have undergone the procedure with no pregnancies to date. Most of the procedure is done with the fingers to avoid lesions to the ovary and tube; the steps are briefly described and diagrammed. 1 or 2 silk stitches hold the ovary in place. The surgical technique is simple and rapid, postoperative complications were absent and recovery was the same as that following any cesarean operation. After periods of up to 6 months no pregnancies have been reported. No menstrual or other alterations attributable to the procedure have been identified. It is expected that patients will be followed up for several years to demonstrate the safety and effectiveness of the procedure, as well as its reversibility if some patients desiring restored fertility undergo reversal operations and and achieve pregnancy.^ieng

[Control of fertility with microdoses of D'norgestrel]. / Control de la fertilidad con microdosis de d'norgestrel.

PIP: 113 multiparous fertile women ranging in age from 20 to 40 with regular menstrual cycles and who had not taken orals for 90 days prior to the trial were given continuous daily doses of 37.5 mcg of D-norgestrel for 4-14 cycles for a total of 1163 cycles of observation. A group of 20 who completed 14 cycles of treatment were given extensive physicals before and after the investigation including endometrial biopsies, vaginal hormone cytology, and blood and liver function tests. None of the patients became pregnant. Side effects were minimal and consisted mainly of headaches and nervousness. The most commonly experienced menstrual irregularities were amenorrhea and short cycles. In 2 cases curettage was done because of continuous bleeding. There was no incidence of thrombosis. There were no important changes in blood count, blood chemistry, urine, or in hepatic function. The biopsies indicated that the drug suppressed ovulation.^ieng

[Study of the basal temperature, cervix mucus, vaginal cytology, spermatic penetration, and length of the menstrual cycle, in patients under clomiphene treatment]. / Estudio de la temperatura basal, moco cervical citología vaginal, penetración espermática y duración del ciclo menstrual, en las paientes en tratamiento con clomifeno.

PIP: 55 patients under clomiphene treatment were studied during 149 cycles. In addition to the usual tests and controls, the authors made a basal temperature curve, took samples of cervical mucus and performed vaginal cytology tests, and calculated the average duration of the cycle. The cycle study based on the Sims Huhner test was also performed on 13 patients. Changes in the results of the tests were found to be related to the dosage and, above all, to the date on which treatment is started. Knowing the changes that occur in the cervical mucus and basal temperature, these 2 tests helped in detecting ovulation. Postcoital cervical sperm penetration improved 1 week after taking the last tablet. The duration of the menstrual cycle increased while taking the drug, and this prolongation of the cycle increased as the drug was administered at a later stage. With respect to vaginal cytology, it is necessary to know the changes that occur in order to interpret the findings correctly; vaginal cytology studies are unreliable in determining the occurrence and especially the probable date of ovulation.^ieng

[Use of the system of progesterone liberation in uterol in dysfunctional uterine bleeding]. / Uso del sistema de liberación de progesterona in utero en sangrados uterinos disfuncionales

PIP: 10 patients, aged 25-46, with dysfunctional menstrual bleeding, were inserted a progesterone-releasing IUD, delivering 65 mcg. of progesterone daily. Complete examinations were carried out before insertion, and after 3 and 6 months. Amount and duration of bleeding diminished in 9 patients; 2 patients presented short periods of amenorrhea. Proliferative endometria changed in secreting endometria, while vaginal cytology with previous estrogenic activity did not change in 2 cases, or insufficiently in 2 more cases. From these results it is concluded that progesterone has a local action at endometrial level, but no systemic collateral actions, and that it can be usefully employed in controlling dysfunctional bleeding.^ieng