Symptoms and behavioral features induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in an old Java monkey [Macaca cynomolgus fascicularis (Raffles)]

The study concerns symptoms and behavioral characteristics induced by MPTP in a 20-year-old Macaca cynomolgus fascicularis, their evolution over 7 months, and the animal's response to 1-dopa treatment. The symptoms which the animal developed include those that have been described earlier in Macaca mulatta and Saimiri sciureus, i.e., rigidity, action tremor, postural tremor, postural flexion, hypokinesia, and bradykinesia. In addition, however, the animal developed a 3.8 Hz resting tremor which in humans is pathognomonic of Parkinson's disease, as well as cogwheeling, the glabellar tap sign, drooling, impaired ability to relax, and many other symptoms. Also unlike previously described MPTP monkeys, the animal's symptoms neither improved spontaneously, nor did they remain stable shortly after MPTP injection. Instead, symptoms steadily progressed to reach a severe status 2 months after MPTP, and further progression was apparent after another 5 months. Therapeutic responses to 1-dopa required accumulation of or kindling by the 100 mg unit doses that were spaced 4 hr apart, were often organized in time as ON episodes that alternated with OFF episodes, and were associated with dyskinesias and bizarre behavior. Of particular interest is that the animal showed kinesia paradoxa which, in humans, constitutes a feature that is unique to Parkinson's disease among the extrapyramidal disorders. In addition to available evidence, the present findings validate the syndrome induced by MPTP in monkey as an animal analogue of Parkinson's disease. Taxonomic category, age, and the occurrence of shock in response to MPTP are discussed as variables that may possibly co-determine the pathology which MPTP may induce in monkey.     

Glutamate and glycine co-activate while polyamines merely modulate the NMDA receptor complex.

1. Agonists may act at any one of three sites on the N-methyl-D-aspartate (NMDA) receptor-effector complex to promote opening of the associated ion channel. The three sites are activated by i) NMDA, L-glutamate, aspartate, and other dicarboxylic amino acids; ii) glycine, D-serine, D-cycloserine, and others; iii) the polyamines spermine or spermidine, but not cadaverine or putrescine. 2. This opening by exogenous agonists is reflected by an enhanced binding of the phencyclidine-like dissociative anesthetic [3H]MK-801 to rat cortical membranes (well washed to remove endogenous agonists, e.g., L-glutamate, glycine). 3. The effects of adding combinations of agonists yielded stimulation approximately equal to the sum of each agonist's effect, suggesting that in the first approximation the three classes act at independent sites. 4. When the glutamate (E) site was antagonized with D-2-amino-5-phosphonopentanoate (D-AP5), no stimulation in binding could be elicited by agonists at the two other sites. Activation of the E site is therefore necessary but not sufficient for channel opening. 5. When the glycine (G) site was antagonized with 7-chlorokynurenate, no stimulation in binding could be elicited by agonists at the other two sites. Activation of the G site is therefore necessary but not sufficient for channel opening. 6. Of the two putative antagonists for the polyamine (PA) site, ifenprodil fails to completely inhibit the binding of [3H]MK-801, whereas arcaine inhibited [3H]MK-801 binding completely. We present data which question the selectivity of arcaine for the polyamine site, and propose that the polyamine site is merely modulatory, but neither necessary nor sufficient, for channel opening.     

Attenuation of opioid induced antinociception by 5-HT1A partial agonists in the rat

The 5-HT1A partial agonists, buspirone, ipsapirone and gepirone did not affect the latency to respond in the tail flick test to heat. However, they strongly attenuated the antinociceptive action of the mu-opioids, morphine and sufentanil. The buspirone metabolite, 1-(2-pyrimidyl)pyridine (1-PP) was ineffective. BMY 7378, spiperone and alprenolol, putative antagonists at 5-HT1A sites, did not modify basal latencies or the action of morphine. TFMPP and mCPP, agonists at 5-HT1B and 5-HT1C sites, also did not affect basal latencies or morphine induced antinociception. These data show that 5-HT1A partial agonists attenuate morphine-evoked antinociception without affecting basal thresholds. They represent an interesting aspect of the interaction between opioids and serotonin in the control of nociception. In addition to opioids (Millan, 1986), serotonin (5-HT) is considered to play a major role in the control of pain and in the expression of opioid analgesia (Roberts, 1984). The identification of a multiplicity of binding sites for 5-HT in the CNS (Fozard, 1987) raises the question of their individual roles in nociceptive processes. The 5-HT1A site is of particular interest since it is present in high concentrations in the dorsal horn of the spinal cord (Daval, Verge, Basbaum, Bourgoin, and Hamon, 1987) and there are conflicting reports that it may mediate analgesia or hyperalgesia (Berge, Fasmer, Ogren, and Hole, 1985, Zemlan, Kow, and Pfaff, 1983). Indeed, the 5-HT1A agonist, 8-OH-DPAT, was reported to attenuate morphine-evoked antinociception in mice (Berge et al., 1985).(ABSTRACT TRUNCATED AT 250 WORDS)     

Systemic amyloidosis: diagnosis before treatment.

Familial amyloidotic polyneuropathy is a systemic amyloidosis with a dismal prognosis for which a surgical treatment exists. Awareness of the clinical characteristics of the disease is critical for early genetic diagnosis and timely referral for liver transplantation. In this report we describe the history of a 49-year-old man in whom non-AA amyloidotic infiltration of the heart and the intestinal tract was diagnosed. Initially, inappropriate identification of the etiology of the disease led to maltreatment.     

Fryns syndrome without diaphragmatic hernia?

We report on a child with Fryns syndrome including lung hypoplasia, characteristic facial appearance, cleft palate, cardiac anomaly, distal limb abnormalities, absent nipples, bicornuate uterus and early death. In contrast to most patients with Fryns syndrome, diaphragmatic hernia was absent in our patient. However, the diaphragm was reduced to a fibrous web with reduced muscular component.     

Limb-body wall complex: 4 new cases illustrating the importance of examining placenta and umbilical cord

Limb-body wall complex (LBWC) is a rare, sporadic, congenital defect defined as a combination of at least two of three characteristics: 1. limb defects, 2. anterior body wall defects, and 3. exencephaly or encephalocoele with/without facial clefts. Three pathogenic mechanisms have been proposed: early amnion rupture, vascular disruption and embryonic dysgenesis. In this study we carried out the pathological evaluation of four fetuses with LBWC and their placentas. None of the cases had craniofacial defects. Three fetuses showed an abdominal wall defect with eventration of abdominal organs, cloacal exstrophy, absent external genitalia, abnormal internal genitalia, scoliosis and lower limb defects. One fetus showed failure of closure of both thoracic and abdominal walls with ectopia cordis, evisceration of left lung and abdominal organs, severe reduction defect of left arm, but normal colon, anus, bladder, genitalia and lower limbs. All cases had a short, malformed umbilical cord, incompletely covered by amnion. The umbilical vessels were embedded in an amniotic sheet which connected the skin margin of the anterior body wall defect to the placenta. These anomalies suggest an abnormal body stalk development as a pathogenic mechanism for LBWC. Prenatally, the abnormal fetoplacental attachment can be detected ultrasonographically by the end of the first gestational trimester. Postnatally, the examination of placenta, umbilical cord and membranes is crucial in confirming the diagnosis of LBWC.     

Comparison between testosterone oenanthate-induced azoospermia and oligozoospermia in a male contraceptive study. IV. Suppression of endogenous testicular and adrenal androgens

Administration of supraphysiological doses of testosterone to normal men causes inhibition of spermatogenesis, but while most become azoospermic, 30-55% maintain a low rate of spermatogenesis. We have investigated whether there are differences in endogenous androgen production, of testicular and adrenal origin, which may be related to the degree of suppression of spermatogenesis. Thirty-three healthy Caucasian men were given weekly i.m. injections of 200 mg testosterone oenanthate (TE), 18 became azoospermic, while 15 remained oligozoospermic. Urinary excretion of epitestosterone, a specific testicular product, was reduced to <10% of pretreatment values, with no differences between the groups. Similar results were obtained for other markers of testicular steroidogenesis. Urinary and plasma adrenal androgens were also reduced during TE treatment: a statistically significant decrease in both (P < 0.001 and P < 0.05 respectively) was seen in the azoospermic but not oligozoospermic responders. These results suggest that testicular steroidogenesis is decreased to <10% by the administration of supraphysiological doses of exogenous testosterone. Differences in the degree of ongoing steroidogenesis in the testis do not appear to account for incomplete suppression of spermatogenesis, thus differences in androgen metabolism may underlie this heterogeneous response. A small but significant reduction in secretion of adrenal androgens was also detectable, the relevance of which is unclear.