Pattern of regional cerebral blood-flow changes induced by acute heroin administration--a perfusion MRI study.

PURPOSE: Although both the subjective and physiological effects of abused psychotropic substances have been characterized, less is known about their effects on brain function. We examined the actions of intravenous diacetylmorphine (heroin), the most widely abused opioid, on regional cerebral blood flow (rCBF), as assessed by perfusion-weighted MR imaging (PWI) in a double-blind and placebo-controlled setting. MATERIAL AND METHODS: Eight male subjects dependent of diacetylmorphine (mean age 36 years, range: 26 to 44 years), who had participated in a clinical diacetylmorphine maintenance program, underwent PWI with gadolinium injection. At two sessions separated by 2-7 days, the participants were examined 80 s after intravenous administration of either diacetylmorphine or saline. rCBF in four regions of interest (amygdala, vermis of the cerebellum, anterior cingulated cortex and thalamus) was compared with heroin versus placebo. RESULTS: In the cerebellum, thalamus and cingulated cortex, there were no significant differences in perfusion values between diacetylmorphine and placebo. In the amygdala, perfusion values were 0.8+/-0.4 and 0.5+/-0.2 on the left, and 0.9+/-0.4 and 0.6+/-0.3 on the right, with diacetylmorphine and with placebo, respectively (t-test results were P=0.044 and P=0.033 on the left and right sides, respectively). Other differences in perfusion values between the drug and placebo did not reach statistical significance. CONCLUSION: Perfusion MRI demonstrated differences in brain hemodynamics induced by drug intake.

Production of a cytotoxin from phorbol myristate acetate-treated human promyelocytes.

Human promyelocytic leukemia cells, when differentiated into macrophages by treatment with phorbol myristate acetate, secrete a cytolytic factor. Enhanced production was achieved when the cultures were treated with bacterial lipopolysaccharide (LPS). Production of the factor was inhibited when cultures were treated with dactinomycin immediately after LPS treatment. Tritirachium alkaline proteinase treatment inactivated the factor, indicating that it has an essential protein moiety. The molecular weight was found to be approximately 40,000 by Sephacryl S-200 gel filtration. The factor was stable at 56 degrees C for 30 minutes, but 80% of the activity was inactivated at 70 degrees C in 30 minutes. The factor was destroyed (96%) by dialysis against 0.01 M HCl (pH 2) for 14 hours. The cytolytic factor had little activity on normal fibroblasts, but it was able to significantly kill transformed cells in vitro.

Light therapy in seasonal affective disorder is independent of time of day or circadian phase.

OBJECTIVE: We tested the hypothesis that phase-delayed circadian rhythms underlie seasonal affective disorder (SAD) by measuring phase position of 6-sulfatoxymelatonin excretion and comparing antidepressant response to morning or evening light given as a first treatment. DESIGN: Randomized controlled trial. SETTING: Ambulatory. PATIENTS: Thirty-two women and seven men with SAD. INTERVENTION: Light therapy (2500 lux for 1 hour for 1 week) was administered either at 7 AM or 10 PM, preceded by a baseline week and followed by a withdrawal week. RESULTS: Our SAD patient sample was moderately depressed (Hamilton Depression Scale [HAM-D] score 18); a HAM-D reduction of 50% or more was found in 12 of 18 patients given morning and in 15 of 21 patients given evening light (70% response rate). Response was not dependent on age, gender, stage of the menstrual cycle, time of year, or on the timing or duration of sleep. Urinary 6-sulfatoxymelatonin was measured in 30 patients; 22 had phase-delayed circadian rhythms. However, phase position was correlated neither with depth of depression nor with a preferential response to morning or evening light. COMMENT: Both morning and evening light therapy improved depressive symptoms in patients with SAD independent of their circadian phase or sleep timing. These findings argue against a circadian phase-delay hypothesis of the pathophysiology of SAD, or the necessity of a phase-advance by morning light for clinical efficacy. They additionally suggest more practicable and flexible schedules for light therapy in SAD, since time of day is not crucial.

[Psychiatric and psychosocial emergency situations]. / Psychiatrische und psychosoziale Notfallsituationen.

Psychiatric emergencies and crises are unforseeable by nature and can have devastating consequences. They can arise both in the course of chronic mental illness and in people who had not shown any previous signs of mental illness. Conditions that are so similar that they might be confused with one another can be caused by a wide range of internal illnesses, adverse side-effects of medications or intoxication. This is the reason why establishing a psychiatric diagnosis in emergency situations must be primarily driven by the question as to whether the differential diagnosis is an internal illness or rather intoxication. The most prevalent psychiatric emergencies in clinical practice are nervous breakdowns, psychomotor agitation and violence, suicidal tendencies, delirium, psychoses as well as addictions.

Animal models and ethological strategies for early drug-testing in humans.

The preclinical evaluation of psychotropic drugs relies on the use of animal tests which are thought to generate clinically relevant information concerning the psychiatric condition for which the drug can be used. Despite their importance, views on the usefulness of animal "models" vary widely, ranging from outright negation on the grounds that human minds are unique, to the more biological view that because of a partially common phylogenetic history, animals share many behavioural features with humans, e.g. learning, attention, aggression or sociality, which are altered in psychiatric disorders. The widespread use of ethology with its emphasis upon the function and origin of behaviour, particularly social behaviour, is based upon this evolutionary view. Many ethopharmacological tests in animals use situations which bias the animal's behaviour towards flight or sociality but their validation requires clinical feedback from humans. Unfortunately, information relating to human social mechanisms is rarely obtainable from conventional clinical-assessment schemes. To help overcome this problem, we have applied ethological principles to a new Challenge Interview Situation which is designed to bias the behaviour of healthy subjects towards flight. Analysis shows that by staring, moving closer or asking the subjects to relate emotional experiences, shifts in non-verbal behaviour towards avoidance and mild social withdrawal are achieved which resemble behavioural strategies recorded ethologically in depressed patients as well as animals in an arrested flight situation. The Challenge Interview is intended for early drug studies in humans where sociality is a target and can be adapted for concomitant endocrine and biochemical studies if required.

Triazolam concentration-effect relationships in healthy subjects.

Triazolam was used to study the plasma concentration-effect relationship of a benzodiazepine because it has a very short plasma t1/2. A standard hypnotic dose of 0.25 mg was given by mouth to six healthy subjects, and blood samples were drawn when the subjects had to perform a battery of psychologic tests. Only the digit-symbol substitution test, the card-sorting test according to numbers, and the visual analog scale (energetic-lethargic) gave significant results. Analysis of the concentration-effect relationship in individuals indicated a wide scatter of the data. Mean values revealed a trend for a learning effect in the card-sorting test. The results are consistent with the hypothesis that triazolam is well suited for a study of concentration-effect relationships, but better psychologic tests would be desirable.

Pharmacodynamics and pharmacokinetics of khat: a controlled study.

OBJECTIVES: To show the subjective and cardiovascular effects of khat leaves having a standardized content of cathinone. BACKGROUND: The main effect of khat is an increase of energy and alertness. This effect is thought to be attributable to the phenylalkylamine cathinone, but no controlled clinical trials have been published. DESIGN: The design was balanced and double blind. Six drug-naïve volunteers received a single dose of khat corresponding to 0.8 mg/kg body weight, as well as alkaloid-free khat as a placebo. Psychologic effects were evaluated by the Addiction Research Center Inventory (ARCI) and visual analog scales. Physiologic measures were systolic blood pressure, diastolic blood pressure, and heart rate. Plasma concentrations of cathinone and its metabolites norephedrine and R,R-(-)norpseudoephedrine were determined by HPLC. RESULTS: Maximal plasma concentrations of cathinone (127 +/- 53 [SD] ng/ml) were attained after 127 +/- 30 minutes. The area under the plasma concentration-time curve from 0 to 9 hours was 415 +/- 207 ng/ml.hr, and the terminal elimination half-life was 260 +/- 102 minutes. An effect of khat was observed in the ARCI scales Abuse Potential (p < 0.01), Motor Stimulation (p < 0.02), Amphetamine-Like Effect (p < 0.005), and Stimulation-Euphoria (p < 0.005), as well as in the visual analog scales Excited-Calm (p < 0.001) and Energetic-Lethargic (p < 0.001). CONCLUSIONS: Our results provide objective evidence for the amphetamine-like stimulatory effects of khat leaves. These effects were closely similar to those observed after cathinone, 0.5 mg/kg body weight, although peak plasma concentrations of cathinone after khat were delayed.

A photometric and plaque assay for macrophage mediated tumor cell cytotoxicity.

Pretreatment of L-929 cells for 2-3 h with 2 micrograms/ml actinomycin D followed by washing rendered them exceedingly sensitive to the direct cytotoxic effects of murine and rabbit macrophages. We exploited the tremendous increase in sensitivity of L-929 cells to effector cell mediated cytotoxicity by demonstrating simple and convenient photometric and plaque assays capable of being completed in 18 h for the quantitation of macrophage mediated tumor cell killing. The plaques demonstrated were generally visible to the unaided eye and were linearly related to the number of effector cells plated indicating that a plaque represented multitarget cytolysis attributed to a single effector cell. Unlike previously described assays, the effector:target ratios demonstrated were extremely low. Using the described techniques, it was estimated that a single macrophage could kill from approximately 10 to 1000 actinomycin D pretreated and washed target cells. In the presence of LPS-activated effector cells, the majority of these targets that stained with eosin Y did so in a cluster pattern, indicating cytotoxicity rather than mere detachment from the monolayer surface.

Modulation of porcine peripheral blood-derived macrophage functions by in vitro infection with African swine fever virus (ASFV) isolates of different virulence.

Macrophages play an important role in defense against invading pathogens and neoplastic diseases. Their ability to maintain their functional characteristics is also important in the survival of the host. Loss of macrophage function during infection may be important in determining resistance or susceptibility of a host species. In this communication, we describe the effect of ASFV replication, in macrophages in vitro, on the functional characteristics of these cells. Infection with ASFV did not alter the expression of Fc receptors nor their ability to mediate ADCC. However, African swine fever virus was shown to modulate antibody mediated phagocytosis, chemiluminescence and chemotaxis. Similar modulation of certain macrophage functions was observed with ASFV isolates that differed in their virulence. We were therefore, unable to correlate the virulence of ASFV with the ability to alter macrophage function.

Influence of diazepam and methylphenidate on identification of rapidly presented letter strings: diazepam enhances visual masking.

The effect of diazepam (0, 5, 10 mg) and methylphenidate (0, 5, 10 mg) on the identification of briefly displayed letter strings composing words was investigated. Each letter was presented for 70 ms. The interstimulus interval (ISI) between two successive letters was 10, 100 or 200 ms. The length of the words (WL) was three, five, seven or nine letters. The dependent variable was the number of correctly identified words. As predicted, strong visual masking effects, the strength of which was dependent on ISI and WL, appeared. In the 10 ms condition, diazepam at both doses, but not methylphenidate, further enhanced masking. It is suggested that the results reflect the effect of GABA on masking, and support certain psychological theories about the inhibitory neuronal pathways that are involved in masking. The human peripheral visual system is a promising model for the experimental assessment and integration of pharmacodynamic, neurophysiological and psychological observations.

Specific effects of the benzodiazepine midazolam on visual receptive fields in light and dark adapted human subjects.

Psychophysical experiments in humans have revealed similar characteristics of visual receptive fields as were found in cats and monkeys from retinal ganglion cell recordings. In addition, in some retinal ganglion cells of cats the GABA antagonist bicuculline decreases the activity of the inhibitory surround. These findings led to two predicitions: 1) benzodiazepines will selectively increase the inhibitory surround of human visual receptive fields, 2) after dark adaptation, no free GABA will be available in the synapses and benzodiazepines will have no effect on the visual system. Characteristics of human receptive fields were determined by subthreshold summation: the contrast threshold of a vertical line was measured dependent on the distance of two parallel flanking lines whose contrast was below threshold. Both hypotheses were confirmed: the threshold in the inhibitory region of receptive fields was specifically increased in a dose-dependent manner by midazolam PO (7.5 mg: P < 0.05; 15 mg: P < 0.01). In dark-adapted subjects no effect of midazolam was found. Control experiments with atropine (1 mg IV), sulpiride (100 mg IM), and levodopa (100 mg PO) showed no specific effect. The visual system may be a model to bridge the gap between animal and human psychopharmacology.

The prevention and correction of hypocalcemia in the parathyroidectomized rat by portacaval shunt.

Adult rats underwent end-to-side portacaval shunt either 30 days prior to or 12 days following parathyroidectomy. When portacaval shunt was performed initially, the serum calcium failed to decrease following subsequent parathyroidectomy and remained within normal levels up to 110 days. When parathyroidectomy first was done, the significant hypocalcemia was corrected subsequently by portacaval shunt and serum calcium remained close to the normal level up to 75 days. The effect of portacaval shunt depended on the calcium content of the food and was obtained only when rats were fed by a regular diet. Rats on a calcium-deficient diet were hypocalcemic, similar to the parathyroidectomized rats without the portacaval shunt. Prolonged calcium-deficient diet alone, without parathyroidectomy, did not by itself result in hypocalcemia either in the intact rat or in the portacaval shunted rat. The data indicate that portacaval shunt prevents and corrects hypocalcemia in the parathyroidectomized Lewis rat as long as sufficient calcium is available in the diet.

MacLeod revisited: sperm count distributions in 374 fertile men from 1971 to 1994.

OBJECTIVES: There has been an enormous amount of interest as to whether sperm counts are declining over time. We sought to compare a contemporary group of fertile men to those from the MacLeod study of 1951 to ascertain whether sperm counts in fertile men have changed over time. METHODS: We obtained sperm count data from 374 fertile men who banked sperm in Minnesota prior to vasectomy from 1971 to 1994 and compared them to sperm count distributions from the 1000 fertile men of MacLeod's study. Semen analyses were performed as per World Health Organization guidelines using identical techniques in both the present and MacLeod studies. RESULTS: The contemporary group had a mean sperm count of 102 +/- 81 x 10(6)/mL (median 85 x 10(6)/mL) compared to 107 +/- 74 x 10(6)/mL (median 90 x 10(6)/mL) for MacLeod's data. There are no significant differences in mean or median sperm counts or sperm count distributions between the groups. CONCLUSIONS: We find remarkable similarities in sperm count distributions in cohorts of fertile men from 1951 and 1971 to 1994. Sperm counts in fertile men have not changed appreciably in the 40 years since MacLeod's report.

Worldwide variations in sperm counts.

OBJECTIVES: Based on the premise that various human disease processes manifest differently depending on geography, we set out to determine whether sperm counts vary from different nations and different regions within the United States. METHODS: We reviewed the literature of all significant population-based studies that evaluated sperm counts from fertile or presumably fertile men from 1930 to the present. RESULTS: We found that sperm counts did, in fact, vary greatly. Throughout the United States, average sperm counts ranged from a low of 48 million/cc in lowa to a high of 134 million/cc in New York, with multiple values in-between from Texas, Minnesota, Washington State, and California. Internationally, average sperm counts ranged from a low of 52.9 million/cc in Thailand to a high of 102.9 million/cc in France. CONCLUSIONS: We conclude that sperm counts are subject to a wide range of variation among geographic locations.

Simplified gonadotropin-releasing hormone (GnRH) stimulation test.

Provocative gonadotropin-releasing hormone (GnRH) stimulation testing indirectly assesses testicular function with more sensitivity than determination of basal gonadotropin levels alone. Unfortunately, the drawbacks of multiple blood sampling and high cost have limited the clinical usefulness of this test. We herein present a simplified, two-point, thirty-minute GnRH stimulation test. Statistical analysis of data from 55 men with normal baseline gonadotropin levels, reveal that this simplified test is just as accurate as the traditional test (p less than 0.0001) without the latter's attendant difficulties. In addition, we found that normal basal gonadotropin levels had little correlation to the actual responses obtained from GnRH stimulation testing (r = 0.20 and r = 0.39 for luteinizing hormone and follicle-stimulating hormone, respectively).

Incidence of external spermatic veins in patients undergoing inguinal varicocelectomy.

OBJECTIVES: To determine the incidence of external spermatic veins at inguinal varicocelectomy. METHODS: A prospective study was performed by making intraoperative observations on 78 varicocelectomies (47 patients) performed by a single surgeon. All patients were referred for evaluation of male infertility and had a palpable varicocele present when examined while performing a Valsalva maneuver in the upright position. Varicocelectomies were performed via the inguinal approach using x 2.5 loupe magnification. Presence of external spermatic veins was defined as visualization (with x 2.5 loupe magnification) of veins on the floor of the inguinal canal traveling posterolateral to the spermatic cord that then subsequently exited the spermatic cord before passing through the internal inguinal ring. Age, anesthetic technique, and need for incision of the external inguinal ring were also recorded for each patient. RESULTS: One third of patients had undergone left-sided varicocelectomies, while two thirds had undergone bilateral procedures. External spermatic veins were identified in 15% of left-sided varicoceles and 19% of right-sided ones. Of 31 patients undergoing bilateral varicocelectomies, 19% had at least 1 external spermatic vein. Of these patients, only 2 (7%) had a unilateral right external spermatic vein, none had a unilateral left external spermatic vein, and 4 (13%) had bilateral external spermatic veins. Overall, of all patients studied, 16% had at least 1 external spermatic vein. Follow-up at 1 year showed no evidence of clinical recurrence in any patient. CONCLUSIONS: These results emphasize the importance of distal gonadal venous anatomy in the surgeon's choice of the proper approach to varicocele repair, since external spermatic veins are only accessible via an inguinal approach.

Geographic variations in sperm counts: a potential cause of bias in studies of semen quality.

OBJECTIVE: To determine whether geographic variations in sperm counts might bias conclusions drawn from studies of semen quality. DESIGN: Reanalysis of published data from a meta-analysis of 61 studies from 1938 to 1990 that concluded a worldwide decline in semen quality over the last 50 years. MAIN OUTCOME MEASURES: Influence of geographic location on sperm counts. RESULTS: Of 61 studies in the meta-analysis, only 20 included > or = 100 men. These 20 studies collectively comprised 91% of the total men studied. We focused our reanalysis on these 20 studies. Of the studies before 1970, all were from the United States and 80% were from New York. These studies represented locations with the highest sperm counts. In contrast, after 1970, 80% of the studies were from locations not represented earlier, including five studies from third world countries, where sperm counts were low. CONCLUSIONS: Sperm counts vary dramatically among different geographic locations.

Accuracy of semen counting chambers as determined by the use of latex beads.

OBJECTIVE: To assess the accuracy of the Hemacytometer (Hausser Scientific, Horsham, PA), Makler (Sefi-Medical Instrument, Haifa, Israel), Cell-VU (Millennium Sciences Inc., New York, NY), and Micro-Cell chambers (Conception Technologies, San Diego, CA) counting chambers. DESIGN: A solution containing a known concentration of latex beads was used as the standard to perform counts on the four different counting chambers. MAIN OUTCOME MEASURES: Bead counts for the four different chambers were compared with the bead counts of the standard solution. Variability within chambers also was determined. RESULTS: Mean bead concentrations for both the Cell-VU and Micro-Cell chambers were consistently similar to the bead concentration of the standard solution. Both the hemacytometer and the Makler chambers overestimated the actual bead concentration of the standard solution by as much as 50% and revealed significant interchamber variability. CONCLUSIONS: Our data revealed marked differences in the accuracy and reliability of the different counting chambers tested and emphasized the need for standardization and quality control of laboratory procedures.

Semen analyses in 1,283 men from the United States over a 25-year period: no decline in quality.

OBJECTIVE: To determine whether semen quality has changed in the United States over the last 25 years. DESIGN: Retrospective review. SETTING: Three U.S. sperm banks, Cryogenic Laboratories, Inc. (Roseville, Minnesota), Idant Laboratories (New York, New York), and California Cryobank, Inc. (Los Angeles, California). INTERVENTION: None. MAIN OUTCOME MEASURES: Age at sample collection, sperm concentration, volume, motility, and days of abstinence before sample collection were determined for each man. Linear and multiple regression analyses were used to assess changes in these characteristics over time. RESULTS: Controlling for the effects of age and duration of abstinence, there was a slight but significant increase in mean sperm concentration but no change in either motility or semen volume over the 25-year period. Both sperm motility and semen volume decreased with increasing age at sample collection. Both sperm concentration and semen volume increased as a function of duration of abstinence. There were significant differences in mean (+/- SEM) sperm concentrations (10(6) sperm/mL) and motilities between the different sperm banks with California lowest (72.7 +/- 3.1, 51.4% +/- 1.1%, respectively), Minnesota higher (100.8 +/- 2.9, 56.0%, respectively), and New York highest (131.5 +/- 3.5, 58.2% +/- 0.5%, respectively). CONCLUSIONS: Our data show no decline in sperm counts over a 25-year period in 1,283 men who banked sperm before vasectomy at three distinct geographical sites in the United States.

Infection and pyospermia in male infertility. Is it really a problem?

Controversy exists concerning the exact role of genitourinary tract infections in male infertility. This ambiguity is due to the currently conflicting literature coupled with present limitations in obtaining and evaluating the significance of diagnostic tests such as semen cultures and leukocyte counts. In the evaluation of the infertile man for a possible infectious cause, a complete history, physical examination, and urinalysis identify most infectious disorders. In the majority of infertile men who are asymptomatic, evaluation for a subclinical genital tract infection focuses on the accurate determination of seminal leukocytes. The determination of pyospermia may identify those men with a subclinical genital tract infection who require further investigation. Prospective studies using clearly defined criteria, new diagnostic tools, and effective control groups are needed to evaluate better the impact of infection and pyospermia on male infertility.