Microwave-assisted Rydberg electromagnetically induced transparency.

We demonstrate electromagnetically induced transparency (EIT) in a four-level cascade-like system, where the two upper levels are Rydberg states coupled by a microwave field. A two-photon transition consisting of an off-resonant microwave field and an off-resonant optical field forms an effective coupling field to induce transparency of the probe light. We characterize the Rabi frequency of the effective coupling field, as well as the EIT microwave spectra. The results show that microwave-assisted EIT allows us to efficiently access Rydberg states with relatively high orbital angular momentum ℓ=3, which is promising for the study of exotic Rydberg molecular states.

Microwave-assisted Rydberg electromagnetically induced transparency: publisher's note.

This publisher's note corrects an error on page 1 in Opt. Lett.43, 1822 (2018).OPLEDP0146-959210.1364/OL.43.001822.

Microwave transitions in pairs of Rb Rydberg atoms.

We have observed microwave transitions between pairs of cold Rb atoms, specifically, transitions between the molecular nd(5/2)nd(5/2) and (n+1)d(j)(n-2)f states for 41≤n≤44. (We use the separated atom limits as labels.) The transition is allowed because the dipole-dipole induced configuration interaction between the nd(5/2)nd(5/2) state and the energetically close (n+2)p(3/2)(n-2)f state leads to an admixture of the latter into the former. Such transitions may provide a way of selecting closely spaced pairs of atoms.

Phase-dependent electron-ion recombination in a microwave field.

Using picosecond laser photoionization of Li in a microwave field we have observed phase-dependent reccombination of the photoelectrons with their parent Li+ ions. Recombination occurs at phases of the microwave field such that energy is removed from the photoelectron in the first microwave cycle after excitation, and there are two maxima in the recombination in each microwave cycle. These observations are consistent with observations made using an attosecond pulse train phase locked to an infrared pulse and with the "simpleman's" model, modified to account for the fact that the photoelectrons are produced in a Coulomb potential.

Studies in porphyria. I. A defect in the reductive transformation of natural steroid hormones in the hereditary liver disease, acute intermittent porphyria.

A variety of 5beta steroid metabolites derived from hormones natural to man are potent inducers experimentally of delta-aminolevulinate synthetase, the rate-limiting enzyme in porphyrin-heme formation. This mitochondrial enzyme is found at high levels of activity in the livers of patients with the genetic disease, acute intermittent porphyria (AIP). In this study the metabolism of (14)C-labeled testosterone was examined in AIP patients to determine whether there was a disproportionate conversion of the hormone to its 5beta, compared to its 5alpha metabolite. The results indicate that AIP subjects do generate a substantially greater than normal fraction of 5beta metabolite from this steroid; the excessive degree of ring A reduction of testosterone taking place via the 5beta pathway in the porphyric patients averages 350% greater than in the nonporphyric subjects. In one asymptomatic AIP patient the disproportionate generation of 5beta metabolite from the hormone reached a level 10 times the normal mean. Studies with a second (14)C-labeled hormone, dehydroisoandrosterone, whose metabolism in man resembles that of testosterone, confirmed the derangement in reductive transformation of steroids found in the individuals carrying the genetic lesion of AIP. These findings define a new endocrine abnormality in AIP patients and raise the possibility that endogenously derived 5beta steroids may contribute by an induction mechanism to the increased levels of hepatic delta-aminolevulinate synthetase activity found in AIP patients.

Studies in porphyria. II. Evidence for a deficiency of steroid delta-4-5-alpha-reductase activity in acute intermittent porphyria.

Patients with the genetic liver disease, acute intermittent porphyria (AIP), have a defect in the reductive transformation of steroid hormones that is manifest by the disproportionate generation of 5beta-steroid metabolites from precursor hormones. 5beta-steroid metabolites were earlier shown to be potent inducers experimentally of delta-aminolevulinate synthetase (ALAS), the mitochondrial enzyme that is rate-limiting in porphyrin synthesis, and that is found at high levels of activity in the livers of AIP patients. In this report, the basis for the defective steroid metabolism in AIP has been shown, through studies with the (14)C-labeled adrenal hormone 11beta-hydroxy-Delta(4)-androstenedione, to reside in a substantial deficiency of hepatic steroid Delta(4)-5alpha-reductase activity. This enzymic deficiency was found in all seven AIP patients studied, and ranged from 34% to as much as 70% below the mean enzyme activity characterizing normal subjects. The functional consequence of the low levels of 5alpha-reductase activity in AIP is to divert the reductive transformation of certain natural hormones from the 5alpha- to the 5beta-pathway; the latter is the metabolic route through which endogenous steroids having the potential for inducing hepatic ALAS are generated. It is not presently known whether the 5alpha-reductase deficiency in AIP is acquired in some fashion or whether it has partial genetic determinants. It seems probable, however, that this enzymatic abnormality, coupled with the dramatic increase in hormone synthesis that occurs at puberty, may be of major importance in determining clinical expression of the latent gene defect for AIP in many individuals. The 5alpha-reductases for steroid hormones are known to be localized in the endoplasmic reticulum of hepatic cells and the present findings in AIP thus represent the first demonstration that an enzymic component of these membranous structures is functionally abnormal in this hereditary liver disease.

Estradiol metabolism in cirrhosis.

Abnormal estrogen metabolism has been found in cirrhosis after administration of intravenous tracers of estradiol-(3)H to 6 patients and 23 healthy controls. The major abnormalities observed involved estrogen metabolites other than the 3 "classic" ones, i.e., estrone (E1), estradiol (E2), and estriol (E3). Urinary recovery of radioactivity was regularly elevated in the patients, to an average of 71% of the dose compared to 51% in normals. This is considered to reflect the component of intrahepatic cholestasis in cirrhosis. The per cent dose recovered as urinary glucosiduronates (42%) was normal in cirrhotics in contrast to impaired glucuronidation of cortisol metabolites in this disease. E1 and E2 were present in normal amounts, and E3 was slightly elevated to 21% of the extract compared to 14% in controls. There were strikingly decreased excretion of 2-hydroxyestrone (3% compared with normal 20%) and 2-methoxyestrone (2% compared with 5%) and increased excretion of 16alpha-hydroxyestrone (12% compared with normal 6%). Thus cirrhosis, too, is characterized by the reciprocal relationship between decreased 2-hydroxylation and increased 16alpha-hydroxylation previously described in hypothyroidism and male breast cancer. However, unlike these latter, the increase of 16alpha-hydroxy metabolites was less than the decrease of 2-hydroxy metabolites. The data indicate clearcut impairment of 2-hydroxylation, suggestive impairment of 16alpha-hydroxylation, and a definite depression of the reaction 16alpha-hydroxyestrone-->estriol, the latter finding so far unique to cirrhosis. Demonstration of abnormal peripheral metabolism of estrogen in cirrhosis provides a new approach to the origin of the hyperestrogenic syndrome in this disease.

Cortisol metabolism in cirrhosis.

The production and peripheral metabolism of cortisol have been studied in 10 cirrhotics and 11 controls after i.v. tracers of cortisol-(14)C. The findings were as follows: (a) Total urinary excretion of radioactivity was normal (81% of the dose) but a decreased fraction was present as glucosiduronates: 18-47% of the dose (average 34%) compared to a normal average of 54%. (b) There was a distinctively abnormal pattern of cortisol metabolites, not previously observed in other illnesses: tetrahydrocortisone was decreased to 14% of the enzyme hydrolysate (normal 26%); cortolones were increased to 34% (normal 19%), owing entirely to an increase in cortolone (20alpha) formation, since beta-cortolone (20beta) was not significantly increased; Reichstein's substances U and epi-U were increased, averaging 2.6% for the former and 4.7% for the latter; tetrahydrocortisol, allotetrahydrocortisol and cortols were normal. This pattern was independent of the degree of decreased glucosiduronate formation and also independent of the presence or absence of a portacaval shunt. (c) Cortisol production, determined by isotope dilution, was normal in each of six cirrhotic patients. From these data, taken in conjunction with our previously reported findings concerning the influence of norethandrolone on cortisol metabolism, the following conclusions were drawn: (a) Cirrhotic patients have decreased A-ring reduction of cortisone to tetrahydrocortisone and correspondingly increased 20-ketone reduction of cortisone to Reichstein's substances U and epi-U and then to the cortolones. (b) Intrahepatic cholestasis, a regular pathophysiological feature of cirrhosis, may be responsible for the observed abnormal cortisol metabolite pattern in this disease. (c) The slowed metabolic turnover rate of cortisol in cirrhosis may be due to decreased transport and/or binding of cortisol to its intracellular metabolic sites rather than to abnormalities of any specific metabolizing enzymes.

A randomized study of the effects of a home diabetes education program.

Home health nurses provided individualized instruction in diabetes self-care within the home environment of 393 diabetic individuals. Each subject was randomly assigned to either the intervention (those receiving home teaching) or control (those not receiving home teaching) group. At 6 mo postenrollment, intervention subjects showed significantly greater self-care knowledge and skills than control subjects, although the actual differences between the two groups in terms of self-care skills were probably too small to have any practical meaning. The primary objective of the study, which was the reduction of the number of preventable diabetes-related hospitalizations (ketoacidosis, ketotic coma, nonketotic coma, insulin reaction, and diabetes out of control), was not achieved; no differences between the groups were noted after 12 mo of follow-up. Similarly, length of hospital stay, foot problems, emergency room and physician visits, and sick days were roughly equivalent in both groups during the follow-up year. These results suggest that, in the absence of concurrent changes in the health-care delivery system and strategies for influencing attitudes toward self-care, education alone is ineffective.

SB 203580 is a specific inhibitor of a MAP kinase homologue which is stimulated by cellular stresses and interleukin-1.

A class of pyridinyl imidazoles inhibit the MAP kinase homologue, termed here reactivating kinase (RK) [Lee et al. (1994) Nature 372, 739-746]. We now show that one of these compounds (SB 203580) inhibits RK in vitro (IC50 = 0.6 microM), suppresses the activation of MAPKAP kinase-2 and prevents the phosphorylation of heat shock protein (HSP) 27 in response to interleukin-1, cellular stresses and bacterial endotoxin in vivo. These results establish that MAPKAP kinase-2 is a physiological RK substrate, and that HSP27 is phosphorylated by MAPKAP kinase-2 in vivo. The specificity of SB 203580 was indicated by its failure to inhibit 12 other protein kinases in vitro, and by its lack of effect on the activation of RK kinase and other MAP kinase cascades in vivo. We suggest that SB 203580 will be useful for identifying other physiological roles and targets of RK and MAPKAP kinase-2.

Manifestations of hypothalamic obesity in man: a comprehensive investigation of eight patients and a reveiw of the literature.

Eight patients are presented in whom obesity developed in association with documented hypothalamic lesions. These lesions included trauma, inflammatory disease, an aneurysm of the internal carotid artery, and five cases of tumor. Detailed metabolic studies were performed in four patients with hypothalamic obesity and in five age- and weight-matched patients with essential obesity(i.e., obesity with no definable etiology). Fasting insulin concentrations were significantly higher in the patients with hypothalamic obesity. During a seven-day fast the insulin levels in patients with essential obesity decreased by 24 to 48 hours, whereas patients with hypothalamic obesity showed a variety of changes; In three out of four of these patients with hypothalamic obesity there was no evidence for hyperplasia of the fat cells. Basal oxygen consumption, body composition, and metabolism of adipose tissue did not differ between the patients with essential obesity and those with hypothalamic obesity. There was no difference in activity of the enzymes in the glycerophosphate cycle. Our data on eight patients with hypothalamic obesity were compared with data on patients in literature. Most cases of hypothalamic obesity occur with space-occupying tumors arising at the base of the hypothalamus. However, trauma, inflammatory diseases, and leukemia are also associated with hypothalamic obesity. Patients with hypothalamic obesity rarely weigh more than 140 kg.

1-substituted 4-aryl-5-pyridinylimidazoles: a new class of cytokine suppressive drugs with low 5-lipoxygenase and cyclooxygenase inhibitory potency.

A series of 1-alkyl- or -aryl-4-aryl-5-pyridinylimidazoles (A) were prepared and tested for their ability to bind to a recently discovered protein kinase termed CSBP and to inhibit lipopolysaccharide (LPS)-stimulated TNF production in mice. The kinase, CSBP, appears to be involved in a signaling cascade initiated by a number of inflammatory stimuli and leading to the biosynthesis of the inflammatory cytokines IL-1 and TNF. Two related imidazole classes (B and C) had previously been reported to bind to CSBP and to inhibit LPS-stimulated human monocyte IL-1 and TNF production. The members of the earlier series exhibited varying degrees of potency as inhibitors of the enzymes of arachidonic acid metabolism, PGHS-1 and 5-LO. Several of the more potent CSBP ligands and TNF biosynthesis inhibitors among the present series of N-1-alkylated imidazoles (A) were tested as inhibitors of PGHS-1 and 5-LO and were found to be weak to inactive as inhibitors of these enzymes. One of the compounds, 9 (SB 210313) which lacked measureable activity as an inhibitor of the enzymes of arachidonate metabolism, and had good potency in the binding and in vivo TNF inhibition assays, was tested for antiarthritic activity in the AA rat model of arthritis. Compound 9 significantly reduced edema and increased bone mineral density in this model.

Recipient selection and evaluation for vascularized pancreas transplantation.

Vascularized pancreas transplantation (PT) is becoming an accepted therapy for selected type I diabetic patients. However, selection and evaluation criteria remain uncertain. In the last 3.5 years, we have interviewed 205 and evaluated 151 diabetic patients for PT. The degree of renal dysfunction (creatinine clearance below 45 ml/min) was used to select patients for combined pancreas-kidney transplantation (PKT) or solitary pancreas transplantation (PTA) (clearance above 70 ml/min). The cardiovascular evaluation (stress thallium study with liberal use of coronary angiography) was used to determine operative risk and provided the other major selection criterion. A total of 104 patients were selected as candidates for PT; 70 have undergone PKT with 98.6% patient survival (1 cardiovascular death), 97.1% kidney graft survival, and 94.2% pancreas graft survival. Thirty-three evaluated patients (24.1%) were not accepted as candidates for PT; 13 have undergone cadaveric kidney transplantation, 5 were placed on the kidney waiting list, and 9 have died. Criteria for PTA include 2 or more diabetic complications or hyperlabile diabetes. Patient (n = 12) and pancreas graft survival after PTA is 83.3 and 50%, respectively. Our conclusion is that a multidisciplinary approach was used for recipient selection for PT based on degree of nephropathy, cardiovascular risk, and presence of diabetic complications. Nearly 75% of diabetic patients evaluated were acceptable candidates for PT. Only 4 (3.8%) of these selected patients died while awaiting or undergoing PT, thus optimizing the use of scarce allograft resources and providing evidence for appropriate patient selection.

Population pharmacokinetics of glyburide in patients with well-controlled diabetes.

STUDY OBJECTIVES: To investigate glyburide pharmacokinetics in patients with well-controlled noninsulin-dependent diabetes mellitus (NIDDM), and test the hypothesis that intersubject variability in the glyburide dose is due to patient differences in the drug's pharmacokinetics. METHODS: Prospective, open-label study. SETTING: University-affiliated, internal medicine outpatient clinic. PATIENTS: Fifty-one patients with NIDDM (11 women, 40 men, mean age 56.7 +/- 15.3 yrs) receiving oral glyburide and with well-controlled glycohemoglobin levels 10.0% or below. INTERVENTION: After fasting overnight, patients ingested their regular morning dose of glyburide and then ate breakfast. Blood samples were drawn before dosing and between 0.5-2 hours, 2-5 hours, and 5-10 hours after dosing. MEASUREMENTS AND MAIN RESULTS: Serum glyburide was assayed by high-performance liquid chromatography and pharmacokinetics by NONMEM. Glyburide clearance was proportional to weight and greater in older patients (> 60 yrs). CONCLUSION: Variability in the glyburide dose was not primarily due to intersubject differences in the drug's pharmacokinetics.

Altered tissue oxygen tension responsiveness in diabetes.

Subcutaneous oxygen tension (tissue PO2) was measured by a polarographic method in the legs of insulin-dependent diabetics (IDDM) and controls. Current flow was measured continuously using a five-stage protocol: baseline; 4 min of complete arterial occlusion; during recovery from ischemia; baseline approximately re-established; induction of hyperemia by local application of heat. Eleven patients with IDDM of 4-32 years of duration, without peripheral arterial disease, were studied and compared with 10 controls. The mean baseline subcutaneous PO2 in diabetics was less than controls; however, the difference was not statistically significant. At the end of arterial occlusion the mean decrease in tissue PO2 was less (P less than 0.025) in diabetics (4.7 +/- 0.9 mm Hg, SEM) compared to controls (10.2 +/- 1.6 mm Hg). With induction of hyperemia the increase in tissue PO2 was lower (P less than 0.001) in diabetics (7.4 +/- 0.4 mm Hg) than in controls (18.6 +/- 1.7 mm Hg). The observed differences provide for the first time direct evidence of altered tissue PO2 responses in diabetes.

Determination of insulin requirements: excessive insulin dosages common in type 1 diabetes mellitus.

OBJECTIVE: To report our experience of determining insulin requirements for initiating continuous subcutaneous insulin infusion (CSII) pump therapy, using an algorithm for intravenous administration of insulin, in patients with poorly controlled diabetes. METHODS: We describe assessment of insulin requirements and analyze data from 27 consecutive admissions. All patients had type 1 diabetes mellitus and were being converted to CSII pump therapy. Twenty-four-hour intravenous insulin requirements were used to initiate CSII pump therapy, and further dose adjustments were undertaken, to optimize glycemic control. Basal, bolus, and total daily insulin requirements were calculated before, during, and 3 months after conversion to CSII therapy. RESULTS: At entry, the mean glycohemoglobin was 11.2% (normal, 5.0 to 8.0%), and the mean daily insulin dose were 45.8 U (0.59 U/kg). Calculated daily insulin requirements using an algorithm for intravenously administered insulin were 37.3 U (0.50 U/kg). At 3 months, mean daily insulin requirements had increased to 39.2 U (0.52 U/kg), and glycohemoglobin improved to 9.4%. Most patients (78%) remained on insulin doses within 10% of the calculated requirements. All patients who were receiving more than 0.6 U/kg daily before assessment required a reduction in insulin dosage to improve glycemic control. CONCLUSION: Many patients with type 1 diabetes are receiving excessive insulin doses. An algorithm for intravenous administration of insulin may be useful for determining requirements and appropriate insulin doses for CSII pump therapy, especially in patients with poor glycemic control.

Boxcar controller for low-repetition-rate use.

We present a simple digital circuit which will control a Princeton Applied Research Corporation (model No. 164) boxcar integrator and thereby allow full utilization of the linear sum mode. This provides for improved signal-to-noise ratios and shorter data acquisition times for short signals [10-50 ns occuring at moderate repetition rates (1-20 Hz)]. This provides significant data acquisition time savings for low-repetition-rate, high-time-resolution measurements. It also increases the signal-to-noise ratio in many circumstances.

The diagnosis of freemartinism in cattle using sex-specific DNA sequences.

The majority of heifers born co-twins to bulls are infertile freemartins. It is important that the condition be diagnosed at an early age as freemartins have no potential for use as replacement stock. A rapid, robust, reliable technique for freemartin diagnosis is described. Three Y-specific polymerase chain reaction (PCR) primer pairs: BOV97M, BRY.1 and AMX/Y were used to detect male cells in the blood of heifers born co-twins to bulls. PCR -based tests have advantages over currently used methods of freemartin diagnosis.

Vitamin supplements and purported learning enhancement in mentally retarded children.

Dr. Ruth Harrell and her colleagues conducted a study in 1981 in which the administration of high dosages of vitamins were determined to dramatically improve the intellectual functioning of mentally retarded children. This paper documents the efforts of its authors to replicate the Harrell et al. research and, although no significant differences were found between active treatment groups and control groups at study's end, a thorough comparison is made between the two research efforts.

A new method for treatment of unresectable, recurrent brain tumors with single permanent high-activity 125iodine brachytherapy.

We describe a new method for treating unresectable recurrent brain tumors in previously-irradiated patients with localized high-dose intracranial brachytherapy of 10,000-30,000 rads using permanent implantation of a single high-activity 125Iodine seed. For unresectable recurrent previously-irradiated pituitary tumors, a single high-activity 125Iodine seed is permanently implanted into the center of the tumor with an interstitial needle inserted under fluoroscopic guidance via a transsphenoidal approach. For unresectable recurrent meningiomas, a single high-activity seed is permanently implanted into the tumor at craniotomy. The clinical course of five patients treated by this method is described. Excellent long-term local control was obtained in all implanted cases. There were no intraoperative, postoperative, or chronic complications.