Filtration performance of three models of N95 filtering facepiece respirators following clinical usage and vaporized hydrogen peroxide decontamination.

BACKGROUND: N95 filtering facepiece respirators (FFRs) are essential personal protective equipment (PPE) for protecting healthcare workers from airborne pathogens. AIM: To perform the first large-scale evaluation of particulate filtration efficiency (PFE) of three models of N95 FFRs following clinical usage and vaporized hydrogen peroxide (VHP) decontamination. METHODS: Three variables were assessed for effect on PFE following VHP decontamination: VHP sterilizer model, N95 respirator model, and prior N95 clinical usage. FINDINGS: The VHP sterilizer model and N95 FFR model impacted PFE performance. Worn N95 FFRs had a 91% lower odds of exhibiting ≥95% PFE compared with the control. CONCLUSION: This work highlights the importance of validating any N95 FFR decontamination programme in its entirety, including prior clinical usage.

Localization and osmotic regulation of vesicular glutamate transporter-2 in magnocellular neurons of the rat hypothalamus.

In this report we present immunocytochemical and in situ hybridization evidence that magnocellular vasopressin and oxytocin neurons in the hypothalamic supraoptic and paraventricular nuclei express type-2 vesicular glutamate transporter, a marker for their glutamatergic neuronal phenotype. To address the issue of whether an increase in magnocellular neuron activity coincides with the altered synthesis of the endogenous glutamate marker, we have introduced a new dual-label in situ hybridization method which combines fluorescent and autoradiographic signal detection components for vasopressin and vesicular glutamate transporter-2 mRNAs, respectively. Application of this technique provided evidence that 2% sodium chloride in the drinking water for 7 days produced a robust and significant increase of vesicular glutamate transporter-2 mRNA in vasopressin neurons of the supraoptic nucleus. The immunocytochemical labeling of pituitary sections, followed by the densitometric analysis of vesicular glutamate transporter-2 immunoreactivity in the posterior pituitary, revealed a concomitant increase in vesicular glutamate transporter-2 protein levels at the major termination site of the magnocellular axons. These data demonstrate that magnocellular oxytocin as well as vasopressin cells contain the glutamatergic marker vesicular glutamate transporter-2, similarly to most of the parvicellular neurosecretory neurons examined so far. The robust increase in vesicular glutamate transporter-2 mRNA and immunoreactivity after salt loading suggests that the cellular levels of vesicular glutamate transporter-2 in vasopressin neurons are regulated by alterations in water-electrolyte balance. In addition to the known synaptic actions of excitatory amino acids in magnocellular nuclei, the new observations suggest novel mechanisms whereby glutamate of endogenous sources can regulate magnocellular neuronal functions.

"Menstrual induction" with Sulproston.

The PGE2-analogue Sulproston (16-phenoxy-omega-17,18,19,20-tetranor-PGE2-mythylsulfonylamide) was administered to 200 medically and gynecologically normal women who were 17 +/- 0.4 days beyond their expected menstrual period and who had a positive pregnancy test. The intramuscular impact dose (500 micrograms repeated after 4 hours) caused an immediate tonic uterine contraction which compromised the estradiol 17 beta, progesterone and chorionic gonadotropin production within the fetoplacental unit, and thereby allowed the evolution of cyclic uterine activity, cervical dilatation and tissue expulsion. Pregnancy termination was complete in 92% of women, 5.5% required surgical curettage and 2.5% were given a second Sulproston treatment 2-3 weeks after the first to remove retained tissue from the uterus. The medical induction of menstruation was preferred by 83% of the women who had previously experienced surgical termination of pregnancy. Normal menstruation resumed in all women after 36 +/- 0.9 days. The majority of 42 women questioned found Sulproston a satisfactory, safe, simple and effective drug regimen for "menstrual induction".

Deactivation of the uterus during normal and premature labor by the calcium antagonist nicardipine.

Nicardipine, a calcium antagonist, suspended the spontaneous activity of the excised rabbit uterus at a concentration of 1 microgram/ml and abolished the electrical excitability at a concentration of 10 microgram/ml. In situ, single doses of 100 and 500 microgram reversibly suspended the spontaneous activity of the postpartum rat uterus (n = 22) for 34 +/- 6 minutes and 94 +/- 9 minutes, respectively. Furthermore, the intrauterine administration of prostaglandin F2 alpha or oxytocin failed to elevate intrauterine pressure in the postpartum rats (n = 18) injected with an average dose of 207 +/- 28 microgram of nicardipine. The administration of nicardipine to the rats (n = 19) immediately after the spontaneous delivery of the first fetus arrested labor, and the delivery of the subsequent fetuses was markedly delayed as compared to the control rats (n = 20). Similarly, when premature labor was induced by ovariectomy (OVX) on day 16, OVX control rats (n = 6) receiving 5 microgram/day of estradiol delivered 82% of the fetuses within 48 hours of OVX, whereas the rats treated with nicardipine (n = 7) delivered only 4% of the fetuses. All fetuses were delivered alive and were normal. Since the estradiol, progesterone, and prostaglandin profiles in the heart plasma, uterine vein plasma, and uterine tissue of the control and experimental rats were similar, the prevention of premature labor resulted from the antagonistic action of nicardipine to calcium.

Endocrine, structural, and functional changes in the uterus during premature labor.

Rats which were subjected to ovariectomy on day 18 of pregnancy and were treated with 17 beta-estradiol underwent delivery prematurely at 0900 +/- 1.9 hours on the morning of day 18. All animals had in plasma and uterine tissue a precipitate and highly significant progesterone withdrawal and a corresponding significant increase in prostaglandin F and prostaglandin F metabolite. Progesterone replacement therapy given to a second group of castrated animals prevented progesterone withdrawal and premature labor, because the hormonal profile in plasma and uterine tissue of these animals was identical with that of the intact pregnant vehicle controls. Electron microscopy of longitudinal and circular myometrial layers showed a precipitate and highly significant increase in the number, size, and area of gap junctions in the uteri of the group undergoing premature delivery. In the uteri of the progesterone-treated and vehicle control groups (both intact pregnant), gap junctions were conspicuously scarce. Thus the extensive regulatory imbalance, provoked by progesterone withdrawal, induced a significant increase in myometrial gap junctions. This structural change established contacts between individual myometrial cell which could transform the multibillion cell community of the uterus into a syncytium, to generate low-resistance pathways to the flow of current and thus promote the propagation of trains of electrical discharge in support of labor.

Relationship between timing of ovariectomy and maintenance of pregnancy in the guinea-pig.

The effect of ovariectomy (OVX) and OVX + progesterone (P) treatment on the regulatory profile and uterine function of the guinea-pig are described. Before day 23 of gestation in the intact pregnant guinea-pig, the placental contribution to P-content is small in comparison with the increasing ovarian contribution. After day 30, the ovarian P-content starts to decrease and the placental P-content exceeds the ovarian contribution, indicating the "luteo-placental shift" (LPS) in P-biosynthesis. Thus, when 14 guinea-pigs were ovariectomized around day 21 of gestation all started aborting within 53 hours of OVX. A gradual increase in intrauterine pressure (IUP), a decrease in P-levels in heart and uterine vein plasma and in the uterine and placental tissues and an increase in the levels of PGF in uterine vein plasma and uterine tissue were observed in these animals. However, if the OVX was delayed until after day 30 of gestation, to examine the biological consequences of advanced LPS in P-biosynthesis, there was no increase in IUP and the animals did not abort in the next 5 days. Furthermore, P-therapy following OVX in the day 21 pregnant guinea-pigs prevented the increase in IUP and the animals did not abort. These observations establish for the guinea-pig a correlation between the success in pregnancy maintenance and the degree of the LPS in P-biosynthesis. These studies therefore emphasize the indispensable role of progesterone in pregnancy maintenance.

Mechanism of action of an orally active PGE1-analogue in pregnant guinea-pigs.

At the 43rd day of pregnancy 6 Experimental guinea-pigs were treated orally with the PGE1-analogue, CP 48,630 (Pfizer), while 6 animals served as vehicle Controls. An average dose of 1.5 mg CP 48,630 compromized the conceptus and provoked abortion in 6.6 +/- 1.4 hours in all 6 Experimental guinea-pigs. The vehicle Controls, with all pregnancies continuing intact, had high P-levels in peripheral and uterine vein plasma, ovaries, placenta and uterine tissue and low PGF-levels in the uterine vein plasma. In contrast, in the Experimental animals the P-levels were significantly reduced and the PGF-levels elevated. Thus, the "PG-Impact" rapidly tipped the regulatory balance of pregnancy, compromized the conceptus (all fetuses were dead and the placentae discolored), and provoked the evolution of uterine activity culminating in abortion.

Gestational changes in the progesterone and prostaglandin F levels of the guinea-pig.

In 87 guinea-pigs the gestational changes were measured in the progesterone (P) and prostaglandin F (PGF) levels of the peripheral and uterine vein plasmas, ovaries, uterus, placenta, fetal membranes and amniotic fluid. In the ovaries, the peripheral and uterine vein plasma, placenta and uterus, P-concentrations increase during early pregnancy and after a plateau decrease significantly as term approaches. In contrast, the uterine-vein PGF-levels remain low throughout pregnancy and only increase near term. Thus, in the guinea-pig, as in the classic species of P-action, normal pregnancy is characterized by high P and low PGF levels and labor by low P and high PGF levels. Of special interest are the additional findings that in the guinea-pig the uterine tissue P-levels are only a fraction of the peripheral plasma levels and the placental PGF-levels far exceed those of the uterus and fetal membranes. To promote the biological interpretation of the endogenous changes in the regulatory profile of the pregnant guinea-pig, current studies examine the functional consequences of the experimentally induced changes in P and PGF-levels.

A rationale for the treatment of dysmenorrhea.

Studies have elucidated the regulatory interplay between ovarian hormonal changes, prostaglandin levels and the evolution of intrauterine pressure that leads to dysmenorrhea. These studies substantiated the premise that primary dysmenorrhea is caused by endogenous prostaglandin excess and prompted clinical trials with naproxen sodium (Anaprox) in patients with primary dysmenorrhea. The primary action of prostaglandin is constriction of uterine blood vessels, with consequent anoxia and sustained myometrial contraction. Cyclic uterine contractions evolve later but gradually, with the progress of time. However, the cyclic contractions are not perceived as painful. It is important to realize that the source of uterine pain in dysmenorrhea is the high resting intrauterine pressure (tonus). Penetration of excess prostaglandins into general circulation fully accounts for the systemic symptoms of dysmenorrhea (nausea, vomiting, diarrhea, headache, etc). Rational treatment of dysmenorrhea should be directed at elimination of the excess prostaglandin action. Naproxen sodium and other prostaglandin synthesis inhibitors decrease intrauterine resting pressure as well as amplitude and frequency of uterine contractions and reduce the uterine concentrations of prostaglandins. These changes are associated with substantial pain relief. Thus, naproxen sodium and other prostaglandin synthesis inhibitors present a logical treatment modality to be used in dysmenorrhea.

The biological meaning of prostaglandin-levels.

Two groups of term pregnant rats, one pretreated with progesterone (P) and another with vehicle only, were induced to deliver with PGF2 alpha. Through an implanted intrauterine (extraovular) catheter 5 microgram PGF2 alpha was injected into each animal every 15 minutes until delivery occurred. If induction fialed the fetuses were removed by hysterotomy. All vehicle controls started delivery within 38.3 +/- 11.7 minutes. In contrast, none of the P-treated rats responded to PGF2 alpha. In all animals uterine vein blood and uterine tissue were collected during labor. Measurements of the P and PGF in uterine vein plasma and uterine tissue showed that the P-treated rats had significantly higher P-levels than the controls (P less than 0.001). In contrast, the PGF-levels were similar in the two groups, but significantly elevated (P less than 0.001) beyond spontaneous labor values. Evidently, the massive elevation of PGF-levels only induces labor when the myometrial action of P is critically reduced and is ineffective when P-action is sustained. Thus, PGF-concentrations cannot be presumed to predict PGF-effect, because the latter is controlled by P.

The biological meaning of progesterone levels.

The effect of systematically delayed progesterone treatment was examined in 45 pregnant rats near term. Progesterone (P) and prostaglandin F (PGF) were measured in uterine vein plasma and uterine tissue before and during spontaneous labor or during prolonged pregnancy. Control animals exhibited the expected P-withdrawal (Pw) prior to spontaneous labor and properly timed P-treatment predictably prevented Pw and labor. However, when P was administered 11.7 +/- 2.8 hours (Mean +/- S.E.) before spontaneous labor, the animals delivered normally despite increased plasma and tissue P-levels. These observations show that P-concentration can not be equated to P-action. Thus, when high P-levels are measured near term, as in parturient women, the biological ACTION of this hormone on uterine function should be cautiously interpreted.

Menstrual induction in preference to abortion.

PIP: In the early 1970s the effort was begun to examine the clinical benefits of "menstrual induction" (MI) at 6 weeks pregnancy (last menstrual period), in the belief that if pregnancy is to be terminated there was no sound medical nor psychological reason to delay the procedure. It was found that the transcervical, intrauterine delivery of a "PG-impact" compromised the conceptus and terminated pregnancy in 95% of the cases, with clinical symptoms of menstruation rather than abortion. The side-effects were acceptable; the prematurity rate did not increase in subsequent pregnancies. Yet, the need for strict asepsis limited the use of this otherwise simple and effective procedure. Recently, this limitation has been overcome by the development of the PGE2 analogue 16-phenoxy-w17,18,19,20 tetranor-PGE2-methyl sulfanylamide ('Sulproston'). Clinical trials have been done in terms of dealing with the questions of efficacy, acceptability, and preference. 90 volunteers have been studied. At 14 days follow-up the success rate (negative pregnancy test) was 96%. The side effects were acceptable -- vomiting 26%, diarrhea 10%, and endometritis 2%. Of the 42 patients interviewed, 90% were satisfied with the procedure. Of those who had previously experienced surgical interruption, 89% preferred this pharmacological method.^ieng

The mechanism of prostaglandin action on the early pregnant human uterus.

To extend observations in 11 weeks pregnant patients the mechanism of prostaglandin (PG) action has been examined in 6 weeks pregnant women (LMP). In 10 gravidas menstrual induction was attempted with a single slow release vaginal suppository containing 3000 microgram (155)-methyl PGF2 alpha methyl ester (U-36,384). In 10 additional gravidas menstruation was provoked by the intramuscular injection of 500 microgram 16-phenoxy-omega-tetranor PGE2 methyl sulfonylamide (Sulproston) at 4 hour intervals, totalling 1250 +/- 154 microgram. The PGF2 alpha and PGE2-analogues provoked similar changes in hormone levels and uterine function, sequentially measured by radioimmunoassays and the recording of intrauterine pressure. However, the effects of the intramuscular regimen developed earlier. Both treatments successfully terminated early pregnancy with clinical symptoms of menstruation if they irreversible compromised the conceptus within 12 hours. However, while both formulations represent advances in postconceptional therapy, only further modifications may closely approximate the "ideal" method of non-surgical menstrual induction.

Induction of preterm labor in the rat by antiprogesterone.

The validity of a new concept, predicting that preterm labor can be induced without oxytocic stimulation by a regulatory imbalance, generated by antiprogesterone (A-P)-provoked P withdrawal (Pw), has been examined in the rat model. At day 19 of pregnancy a single oral dose of the steroidal A-O isoxazol, which inhibits P synthesis, significantly reduced uterine P levels, increased uterine estradiol and prostaglandin F levels, and induced preterm labor. This precocious regulatory imbalance and preterm labor were prevented, by blocking the A-P-induced Pw with P treatment. The regulatory imbalance which triggered the onset of spontaneous labor in the control animals was similar, but it occurred at term rather than before term. The potential of this method in improving the management of medically indicated induction of preterm labor is discussed.

Effect of ibuprofen on menstrual blood prostaglandin levels in dysmenorrheic women.

In a randomized crossover study 15 dysmenorrheic women were treated during two consecutive menstrual period, once with the potent prostaglandin-synthesis inhibitor: ibuprofen and once with an identical looking placebo. Each patient was medicated for 12 hours during the first day of her menstrual flow and was subsequently fitted with a cervical cup for the collection of menstrual blood during three hours. In these samples the concentrations of prostaglandin (PG)F and PGE were measured by radioimmunoassay. The patients receiving placebo had high PGF levels 135 +/- 27 ng/ml (Mean +/- S.E.) which were significnatly reduced by Ibuprofen to 24 +/- 5 ng/ml (P less than 0.001). The PGE concentrations decreased from 5 +/- 1 ng/ml to 2 +/- 1 ng/ml (P less than 0.05). Ibuprofen also reduced the menstrual pain significantly (P less than 0.001). These results substantiate the earlier conclusion that a causal relationship exists between effective treatment with PG-synthesis inhibitors and decrease in menstrual blood PG levels, intrauterine pressure and dysmenorrheic pain.

The mechanism of prostaglandin action on the pregnant human uterus.

The concentrations of 15 methyl PGF2 alpha, progesterone and estradiol in the peripheral plasma were assayed sequentially and the resting and active pressures of the uterus were quantitated in 10 first trimester pregnant patients, treated with a vaginal suppository containing 3 mg U-36,384. The purpose of the study was to determine the sequence of the prostaglandin induced changes in regulatory profile and uterine function and thus expose further the mechanism of prostaglandin action. The temporal relationships of the changes revealed that the primary action of exogenous prostaglandin is the disruption of the normal endocrine function of the conceptus and that the delayed oxytocic effect of this compound is secondary, a consequence of the primary action. Apparently prostaglandins are only effective as postconceptional agents if they convert the refractory normal pregnant uterus into a reactive organ. The academic and therapeutic significance of this finding is discussed.