Measurement of the Positive Muon Anomalous Magnetic Moment to 0.20 ppm.

We present a new measurement of the positive muon magnetic anomaly, a_{µ}≡(g_{µ}-2)/2, from the Fermilab Muon g-2 Experiment using data collected in 2019 and 2020. We have analyzed more than 4 times the number of positrons from muon decay than in our previous result from 2018 data. The systematic error is reduced by more than a factor of 2 due to better running conditions, a more stable beam, and improved knowledge of the magnetic field weighted by the muon distribution, ω[over ˜]_{p}^{'}, and of the anomalous precession frequency corrected for beam dynamics effects, ω_{a}. From the ratio ω_{a}/ω[over ˜]_{p}^{'}, together with precisely determined external parameters, we determine a_{µ}=116 592 057(25)×10^{-11} (0.21 ppm). Combining this result with our previous result from the 2018 data, we obtain a_{µ}(FNAL)=116 592 055(24)×10^{-11} (0.20 ppm). The new experimental world average is a_{µ}(exp)=116 592 059(22)×10^{-11} (0.19 ppm), which represents a factor of 2 improvement in precision.

Dynorphin B and spinal analgesia: induction of antinociception by the cannabinoids CP55,940, Delta(9)-THC and anandamide.

The endogenous opioid dynorphin B was evaluated for its role in cannabinoid-induced antinociception. Previous work in our laboratory has shown that the synthetic, bicyclic cannabinoid, CP55,940, induces the release of dynorphin B whilst the naturally occurring cannabinoid, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), releases dynorphin A. The dynorphins contribute in part to the antinociceptive effects of both cannabinoids at the level of the spinal cord. The present study compares dynorphin B released from perfused rat spinal cord in response to acute administration of anandamide (AEA), Delta(9)-THC and CP55,940 at two time points, 10 min and 30 min post administration, and attempts to correlate such release with antinociceptive effects of the drugs. Dynorphin B was collected from spinal perfusates of rats pretreated with Delta(9)-THC, CP55,940 or AEA. The supernatant was lyophilized and the concentrations of dynorphin B were measured via radioimmunoassay. At a peak time of antinociception (10 min), CP55,940 and Delta(9)-THC induced significant two-fold increases in the release of dynorphin B. AEA did not significantly release dynorphin B. Upon a 30-min pretreatment with the drugs, no significant dynorphin B release was observed, although antinociceptive effects persisted for CP55,940 and Delta(9)-THC. Previous work indicates that Delta(9)-THC releases dynorphin A while AEA releases no dynorphin A. This study confirms that although all three test drugs produced significant antinociception at 10 min, the endocannabinoid, AEA, does not induce antinociception via dynorphin release. Thus, our data indicate a distinct mechanism which underlies AEA-induced antinociception.

Synergistic interactions of endogenous opioids and cannabinoid systems.

Cannabinoids and opioids are distinct drug classes historically used in combination to treat pain. Delta(9)-THC, an active constituent in marijuana, releases endogenous dynorphin A and leucine enkephalin in the production of analgesia. The endocannabinoid, anandamide (AEA), fails to release dynorphin A. The synthetic cannabinoid, CP55,940, releases dynorphin B. Neither AEA nor CP55,940 enhances morphine analgesia. The CB1 antagonist, SR141716A, differentially blocks Delta(9)-THC versus AEA. Tolerance to Delta(9)-THC, but not AEA, involves a decrease in the release of dynorphin A. Our preclinical studies indicate that Delta(9)-THC and morphine can be useful in low dose combination as an analgesic. Such is not observed with AEA or CP55,940. We hypothesize the existence of a new CB receptor differentially linked to endogenous opioid systems based upon data showing the stereoselectivity of endogenous opioid release. Such a receptor, due to the release of endogenous opioids, may have significant impact upon the clinical development of cannabinoid/opioid combinations for the treatment of a variety of types of pain in humans.

Immunosuppression in adult female B6C3F1 mice by chronic exposure to ethanol in a liquid diet.

The overall objective of these studies was to characterize the effects of ethanol on the immunocompetence of adult female B6C3F1 mice. To obtain a significant suppression in the antibody response to SRBC, splenocytes from untreated mice had to be directly exposed to concentrations of ethanol from 0.3% to 3.0%, or to acetaldehyde at concentrations greater than 0.03%. We do not believe that these results are consistent with a role by a direct effect by either ethanol or its primary metabolite because these concentrations are higher than what could be obtained as reasonable blood levels. For in vivo exposure, we employed a pair-feeding regimen which was based on a liquid diet containing 5% ethanol (v/v) that provided 36% of the caloric intake as ethanol. Our results indicated that there was a definite temporal relationship to the consequent suppression of the antibody response to SRBC in that no effect was observed after 14 days exposure, and that the magnitude of the suppression increased from 18% after 21 days to 70% after 42 days. We also monitored the liver for histopathology and observed that the ethanol-induced liver damage was restricted to steatosis (fatty liver), which was also manifested with time and which was most pronounced after 42 days exposure. In contrast to our results with the in vivo antibody response, we saw no effect on mitogen-induced proliferation by splenocytes from ethanol-treated mice. These results prompted us to measure in vitro antibody responses by splenocytes from ethanol-treated mice. We saw no suppression of the in vitro antibody responses to SRBC, DNP-Ficoll or LPS after any length of exposure to ethanol, and speculated that the basis for the suppression of the in vivo antibody response was an indirect consequence of exposure. We subsequently determined that when normal splenocytes were cultured in 5% serum from ethanol-exposed mice (42-day group), there was a > 80% suppression relative to the serum from the pair-fed controls. As important controls for these studies, we have demonstrated that there was no difference between the responses of normal lymphocytes cultured in 5% normal mouse serum and in 5% serum taken from the pair-fed restricted controls. A determination of the ethanol content in the serum from ethanol-exposed mice (42-day group) indicated that the amount of ethanol present in these cultures was < 0.003%.(ABSTRACT TRUNCATED AT 400 WORDS)

Lysis of Neisseria gonorrhoeae initiated by binding of normal human IgM to a hexosamine-containing lipooligosaccharide epitope(s) is augmented by strain-specific, properdin-binding-dependent alternative complement pathway activation.

We studied the specificity of naturally acquired IgM bactericidal for strains of Neisseria gonorrhoeae that varied in sensitivity to the lytic action of normal human serum (NHS) and the relative ability of these strains to deplete the classical (CP) and alternative (ACP) C pathways. Lysis of both highly sensitive and relatively insensitive strains was inhibited by the same gonococcal lipooligosaccharides (LOS), as well as by Salmonella minnesota Re LOS and three hexosamine-containing glycose polymers. A polymer of N-acetylgalactosamine phosphate was the most inhibitory; a polymer of N-acetylglucosamine phosphate only partially inhibited. Neither 3-deoxy-D-manno-octulosonic acid (dOc1A) nor a polymer that contained dOc1A but not hexosamine inhibited NHS lysis. A co-polymer of N-acetylgalactosamine-dOc1A inhibited both bactericidal activity and the binding of IgM to the LOS of a highly serum-sensitive (sers) gonococcal strain. Carboxyl reduction of the dOc1A in this polymer did not affect its inhibitory capacity for gonococcal antibody, but abolished its binding to homologous antibody induced by vaccination. CP activity was not affected by vaccination. CP activity was not affected by absorption of NHS with gonococcal strains, whereas ablation of CP activity markedly but variously diminished lytic activity for highly sers strains. ACP activity was variously depleted by gonococcal strains, and the proportion of bacteria that could be lysed through the ACP varied among strains and among different populations of a given strain. The titer at which a strain was sensitive to NHS lysis was a function of its ACP consumption (p = 0.006), which accounted for 70% of the differences in titer among strains. Analyses of the absorbed sera revealed that the gonococci had variously depleted properdin from NHS as assessed by using an Ag-capture solid-phase RIA. Addition of purified properdin to absorbed sera restored ACP activity to normal levels. Western immunoblots of gonococcal lysates showed that purified properdin bound directly to a 39-kDa outer membrane protein. We conclude that both CP activation by IgM binding to LOS epitopes, one of which contains hexosamine, and ACP activation, which is a function of strain-specific direct binding of properdin, can initiate lysis of sers strains and that ACP activation, also enhances lysis and accounts for variations in sensitivity of sers strains.

Disseminated histoplasmosis in the acquired immune deficiency syndrome: clinical findings, diagnosis and treatment, and review of the literature.

Histoplasmosis is a serious opportunistic infection in patients with AIDS, often representing the first manifestation of the syndrome. Most infections occurring within the endemic region are caused by exogenous exposure, while those occurring in nonendemic areas may represent endogenous reactivation of latent foci of infection or exogenous exposure to microfoci located within those nonendemic regions. However, prospective investigations are needed to prove the mode of acquisition. The infection usually begins in the lungs even though the chest roentgenogram may be normal. Clinical findings are nonspecific; most patients present with symptoms of fever and weight loss of at least 1 month's duration. When untreated, many cases eventually develop severe clinical manifestations resembling septicemia. Chest roentgenograms, when abnormal, show interstitial or reticulonodular infiltrates. Many cases have been initially misdiagnosed as disseminated mycobacterial infection or Pneumocystis carinii pneumonia. Patients are often concurrently infected with other opportunistic pathogens, supporting the need for a careful search for co-infections. Useful diagnostic tests include serologic tests for anti-H. capsulatum antibodies and HPA, silver stains of tissue sections or body fluids, and cultures using fungal media from blood, bone marrow, bronchoalveolar lavage fluid, and other tissues or body fluids suspected to be infected on clinical grounds. Treatment with amphotericin B is highly effective, reversing the clinical manifestations of infection in at least 80% of cases. However, nearly all patients relapse within 1 year after completing courses of amphotericin B of 35 mg/kg or more, supporting the use of maintenance treatment to prevent recurrence. Relapse rates are lower (9 to 19%) in patients receiving maintenance therapy with amphotericin B given at doses of about 50 mg weekly or biweekly than with ketoconazole (50-60%), but controlled trials comparing different maintenance regimens have not been conducted. Until results of such trials become available, our current approach is to administer an induction phase of 15 mg/kg of amphotericin B given over 4 to 6 weeks, followed by maintenance therapy with 50 to 100 mg of amphotericin B given once or twice weekly, or biweekly. If results of a prospective National Institutes of Allergy and Infectious Disease study of itraconazole maintenance therapy document its effectiveness, alternatives to amphotericin B may be reasonable.

Umbilical blood waveforms in fetal surveillance of twins.

Umbilical arterial velocity waveforms were recorded in 69 pairs of twins by means of continuous-wave Doppler analysis and an Angioscan spectrum analyzer. A systolic/diastolic ratio was measured for each twin. The sum of the systolic/diastolic ratio was calculated and the difference between each twin was expressed as the delta systolic/diastolic ratio. Significant differences in delta systolic/diastolic and neonatal weight were previously set at 0.4 and 350 gm, respectively. Sonography was used for fetal age confirmation and diagnosis of fetal growth retardation. All neonates were weighed; at birth gestational age was assigned by Dubowitz criteria and categorized as adequate-, small-, or large-for-gestational age. The sensitivity, specificity, and predictive value of the delta systolic/diastolic ratio were determined. The perinatal implications of this test in the management of twin pregnancy are discussed.

Microbial growth patterns in a total parenteral nutrition formulation containing lipid emulsion.

Microbial growth of Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and Candida albicans was evaluated in a standard amino acid-dextrose-based total parenteral nutrition (TPN) solution, 10% lipid emulsion, and a combined TPN formulation containing amino acids, dextrose, and lipid emulsion. At an initial inoculum of 10(4) CFU/ml, all three bacterial organisms grew well in 10% lipid emulsion, died in the standard solution and grew only minimally or died in the combined formulation. C. albicans grew in all three formulations at an initial inoculum of 10(4) CFU/ml; however, at an initial inoculum of 10(2) CFU/ml, which approximates touch contamination, growth of Candida in the standard and combined formulations was less than 1 log at 24 hr in contrast to the 10% lipid emulsion which showed significant growth greater than 2 log at 24 hr. It is concluded that a 24-hr infusion time is safe for the combined TPN formulation used in this study. This should result in significant cost savings compared to the previously recommended 12-hr infusion time.

Antibody-independent activation of C1 by type Ia group B streptococci.

A prototype fresh clinical isolate of type Ia group B streptococci (strain 515) can be opsonized by serum containing low levels of antibody. This opsonizing process can also occur in hypogammaglobulinemic serum, confirming its antibody independence, but it does require Ca++ ions and the second component of complement (C2). When formalin-fixed organisms are reacted with whole serum, C4 and C3 are cleaved. These data are strong evidence that this organism can directly activate C1 in the absence of antibody and that this activation leads to the formation of a classical C3 convertase (C4b2a), which cleaves C3. The observation that opsonization can occur in hypogammaglobulinemic serum suggests that complement alone, presumably the fixation of C3b, is sufficient for phagocytes to ingest this pathogen.

Ethylenediaminetetraacetic acid-sensitive antiphagocytic activity of Neisseria gonorrhoeae.

Colonial types of Neisseria gonorrhoeae were examined for the presence of pilus-independent antiphagocytic activity. Type 3 and depiliated type 1 gonococci had a shearing- and protease-resistant antiphagocytic activity that was eliminated by treatment with ethylenediaminetetraacetic acid (EDTA) and that was not present on type 4 bacteria. Incubation of EDTA-treated bacteria 37 degrees C for 90 min resulted in fas prevented by antibiotics that block the final assembly of cell wall macromolecules that depend on the C55-isoprenoid carrier for export. These include both lipopolysaccharide and peptidoglycan. Restoration was, however, unaffected by drugs that interfere with the synthesis of peptidoglycan, but not that of lipopolysaccharide, and by inhibitors of protein synthesis. These data suggested that gonococci have an antiphagocytic mechanism in addition to the previously described determinant (presumably pili) that was removed by blending or by treatment with proteases. Of the two antiphagocytic activities, type 1 had both, type 3 had only the EDTA-sensitive component, and type 4 had neither.