Evidence that 3α-hydroxy-5α-pregnan-20-one is a physiologically relevant modulator of gaba-ergic neurotransmission

3α-Hydroxy-5α-pregnan-20-one (HPO) is a progesterone metabolite which exhibits narcotic properties at high concentrations by interactions with the receptor for gamma-aminobutyric acid (GABA). The present investigation characterized low-dose effects of HPO on GABA_A receptor binding, by determining the allosteric properties of HPO on the in vitro binding of ³H-muscimol to membrane fractions from the cerebella of ovariectomized rats. A newly developed method for tissue preparation was used to wash out endogenous ligands interfering with the assay. HPO reduced the affinity of ³H-muscimol to GABA_A receptor sites by 52% and enhanced the number of accessible binding sites from 5.5±0.5 to 7.5±1.3 pmol/mg protein at subnanomolar (0.1 nM) HPO concentrations. The modulatory effects of HPO on GABA_A receptor binding provide evidence that this pregnane steroid might be a physiologically relevant modulator of GABAergic neurotransmission.     

Platelet 5-hydroxytryptamine increases with platelet age in dogs.

Thrombocytopenia was induced in mongrel dogs by two mechanisms: immunologically, by intravenous injection of heterologous antiplatelet antibody, and non-immunologically, by circulating the blood through glass beads in anesthetized animals. The platelet content of 5-HT was monitored before and during the recovery of the blood platelet counts. This period is associated with the normalization of the mean platelet survival time and with a progressive increase in the mean age of the circulating platelet population. A continuous increment in platelet 5-HT closely followed the increase in platelet counts in both models of thrombocytopenia, and a strong correlation was found between the platelet age and 5-HT content. These findings support the concept that platelets accumulate 5-HT during their physiological aging process, contradicting the notion that a negative balance in 5-HT content results at the end of their physiological lifespan in circulation. These results are not in conflict with the concept that circulating platelets release and re-uptake 5-HT.     

Differences in the abilities of human tau isoforms to promote microtubule assembly.

Three isoforms of human tau protein were compared for their abilities to induce microtubule assembly. The three isoforms, tau 3 (tau containing three microtubule-binding domains), tau 4 (tau containing four microtubule-binding domains) and tau 4L (tau containing four microtubule binding domains plus a 58-amino-acid insert near the N-terminus) were expressed in E. coli and purified using ammonium sulfate precipitation, ion exchange, and size exclusion chromatography. All three isoforms induced microtubule assembly at micromolar concentrations and showed similar critical concentrations for assembly of 0.4-0.45 microM. However, tau 4 induced microtubule formation at a rate five- to tenfold faster than either tau 3 or tau 4L. The rate of microtubule elongation seen with tau 4 was twofold greater than with tau 3 or tau 4L, suggesting that the faster rate of microtubule assembly seen with tau 4 was due, at least in part, to faster elongation. Tau 4 induced a greater number of microtubules to form at steady state than did tau 3 or tau 4L. The microtubules generated with each tau isoform had similar steady-state length distributions and were equally susceptible to cold-induced disassembly. These results indicate that the additional microtubule-binding domain in tau 4 enhances microtubule assembly, while the 58-amino-acid insert negates the stimulatory effect of the fourth microtubule-binding domain.     

Development of rostrocaudal dendritic bundles in rat thoracic spinal cord: analysis of cholinergic sympathetic preganglionic neurons.

Using monoclonal antibodies to choline acetyltransferase (ChAT) and glial fibrillary acidic protein (GFAP), we have analyzed the development of the dendritic bundles formed by cholinergic sympathetic preganglionic neurons (SPNs) in relationship to changes in the organization of glial fibers. In adult rat thoracic spinal cord, SPNs in the intermediolateral (IML) and central autonomic (CA) regions extend dendrites in both the mediolateral and rostrocaudal directions, forming a ladder-like pattern in horizontal sections of thoracic spinal cord. We report that, while the mediolateral dendrites form prenatally, the rostrocaudal dendritic bundles are not detected until at least a week later, during early postnatal life. The rostrocaudal dendrites develop rapidly during the first postnatal week, and achieve an adult-like pattern by postnatal day 14. The observed ontogenetic arrangements of dendritic bundles were correlated with the developing organization of astroglial processes with which they are intimately associated. While the appearance of mediolateral dendrites is consistent with the radial organization of glial in the embryonic spinal cord, the developmental time course of the rostrocaudal dendritic bundles coincides with the transformation of glial cells from this predominantly radial or transverse orientation to the randomly-oriented, stellate pattern of mature astrocytes. This temporal association suggests that ontogenetic changes in the organization of glial cells may contribute to the differential development of mediolateral and rostrocaudal dendritic patterns in the spinal cord.     

Physiological responses of typical versus heavy weight triathletes to treadmill and bicycle exercise.

A physiological comparison of the responses of typical weight (less than 90 kg) versus heavy weight (greater than 90 kg) male triathletes to maximal treadmill and maximal bicycle exercise was performed to better understand the effects of weight on endurance performance. The heavy triathlete group (90.9 +/- 3.2 kg, mean +/- SD) had significantly (p less than .01) greater percent body fat (11.9 +/- 3.6 vs 7.4 +/- 1.8%) while having significantly (p +/- .01) lower VO2max values expressed in ml.kg-1.min-1 on both the treadmill (55.6 +/- 4.1 vs 69.9 +/- 5.5) and bicycle ergometer (51.9 +/- 3.9 vs 60.5 +/- 6.2) than the typical triathlete group (66.6 +/- 5.9 kg). Analysis of covariance using body fat as the covariate resulted in persistent significant (p less than .02) VO2max (ml.kg-1.min-1) differences between the groups. Statistically significant (p less than .05) differences in running economy existed between the groups (33.7 +/- 2.7 vs 37.1 +/- 1.5 ml.kg-1.min-1; typical vs heavy). The heavy triathletes also had a significantly (p less than .01) shorter treadmill performance time (9.6 +/- 2.3 vs 13.2 +/- 1.7 min) and significantly (p less than .01) lower power per weight ratio on the bicycle ergometer (5.37 +/- 0.48 vs 6.47 +/- 0.59 watts/kg). These findings indicate that the heavy triathlete is at a physiological disadvantage when competing in endurance events and supports the inclusion of a weight category in these events. The reported triathlon results support these physiological findings.     

Microscopic endonasal surgery of the paranasal sinuses and the parasellar region

The anatomic principles and operative techniques currently applied to functional endoscopic endonasal surgery have allowed for significant refinements in another approach to regional pathology that uses the operating microscope, newly designed sinus instruments, and a self-retaining nasal speculum system. The main benefits of this method are the superb widefield stereoscopic vision and the distinct freedom to work bimanually. Additionally, direct bipolar cautery of bleeders is afforded while use of the observer tube or video allows for excellent teaching. The precise nature of this surgery affords less fear of serious complications in the treatment of periorbital, paranasal sinus, and parasellar diseases. We describe technical aspects of the surgery and associated complications in 219 patients treated from 1984 to 1987.     

Manifestation of malignant lymphoma of the head and neck with special reference to the salivary glands

We found that thirteen per cent of all head and neck malignomas are malignant lymphomas. In 75% of these cases the Non-Hodgkin type could be found. The major salivary glands were involved by the lymphoma in 55% out of 104 patients. Paraglandular lymph nodes of the parotid gland were affected as well as intraglandular lymph nodes and the lymphoid tissue within the gland proper. The submandibular gland normally shows an involvement only with its paraglandular lymph nodes. Two thirds of the Non-Hodgkin lymphomas located in the salivary glands were low-grade. In case of clinical suspicion of a malignant lymphoma, fine needle biopsy is required for cytological diagnosis. However, surgery is mandatory for histological diagnosis, not as a therapeutic measure.     

Temporal summation of repetitive click stimuli

Monaural loudness balances were performed by eight normal-hearing subjects to determine the effect of click repetition rate on loudness sensation. Click trains of 500 msec duration were matched in loudness to a standard 500 msec 1000 Hz tone burst presented at three reference loudness levels (70, 80, and 90 phons). Click trains were presented at repetition rates of 11, 31, 51, and 91 clicks per sec. It was found that click trains at faster repetition rates required lower intensities for judgments of equal loudness sensation. This finding was attributed to the process of temporal loudness summation. The magnitude and nature of the temporal summation process as well as the influence of the reference loudness level are discussed.     

Epidemic measles in an isolated unvaccinated population, India

Between June and September, 1986, an outbreak of measles occurred in Pilkhi Primary Health Centre area (population 56,000) in Tehri Garhwal district, Uttar Pradesh, India. Overall, 1092 cases were identified and 62 died; case-fatality ratio was 5.7%. Illness was restricted primarily to children below 15 years of age; 38% cases were in children under 5 and 58% between 5-14 years of age. To better characterize the outbreak, a survey was conducted in 13 affected villages. The age of the cases ranged from 5 months to 19 years (median = 7.0 years). The age-specific attack rates were 22.4%, 54.5%, 46.2% and 35.3% for children under 1, 1-4, 5-9, 10-14 years of age respectively. In as many as four villages, the attack rate in children below ten was 80% or more. Secondary attack rate among family members was 70%. Overall, 82% of children with measles developed complications which consisted mainly of pneumonia, diarrhoea and dysentery. The age-specific case-fatality ratios in infants and children 1-4 years of age were 23.1% and 11.5% respectively; thereafter the rates tended to decline with increasing age and was higher in females than in males (less than 0.05). Pneumonia which was a complication in 39% of measles cases contributed to 56% of deaths. Traditional beliefs and customs in the area were strong and did not encourage treatment of measles cases. Although a measles vaccination programme has been launched in India since 1985, only 30 districts could be covered during the first year and another 90 during 1986.(ABSTRACT TRUNCATED AT 250 WORDS)