Post-recombination effects in confined gases photoionized at megahertz repetition rates.

Recombination-driven acoustic pulses and heating in a photoionized gas transiently alter its refractive index. Slow thermal dissipation can cause substantial heat accumulation and impair the performance and stability of gas-based laser systems operating at strong-field intensities and megahertz repetition rates. Here we study this effect by probing the pulse-by-pulse buildup of refractive index changes in gases spatially confined inside a capillary. A high-power repetition-rate-tunable femtosecond laser photoionizes the gas at its free-space focus, while a transverse-propagating probe laser interferometrically monitors the resulting time-dependent changes in refractive index. The system allows convenient exploration of the nonlinear regimes used to temporally compress pulses with durations in the ∼30 to ∼300 fs range. We observe thermal gas-density depressions, milliseconds in duration, that saturate to a level that depends on the peak intensity and repetition rate of the pulses, in good agreement with numerical modelling. The dynamics are independently confirmed by measuring the mean speed-of-sound across the capillary core, allowing us to infer that the temperature in the gas can exceed 1000 K. Finally, we explore several strategies for mitigating these effects and improving the stability of gas-based high-power laser systems at high repetition rates.

Efficient single-cycle pulse compression of an ytterbium fiber laser at 10†MHz repetition rate.

Over the past years, ultrafast lasers with average powers in the 100 W range have become a mature technology, with a multitude of applications in science and technology. Nonlinear temporal compression of these lasers to few- or even single-cycle duration is often essential, yet still hard to achieve, in particular at high repetition rates. Here we report a two-stage system for compressing pulses from a 1030 nm ytterbium fiber laser to single-cycle durations with 5 µJ output pulse energy at 9.6 MHz repetition rate. In the first stage, the laser pulses are compressed from 340 to 25 fs by spectral broadening in a krypton-filled single-ring photonic crystal fiber (SR-PCF), subsequent phase compensation being achieved with chirped mirrors. In the second stage, the pulses are further compressed to single-cycle duration by soliton-effect self-compression in a neon-filled SR-PCF. We estimate a pulse duration of ∼3.4 fs at the fiber output by numerically back-propagating the measured pulses. Finally, we directly measured a pulse duration of 3.8 fs (1.25 optical cycles) after compensating (using chirped mirrors) the dispersion introduced by the optical elements after the fiber, more than 50% of the total pulse energy being in the main peak. The system can produce compressed pulses with peak powers >0.6 GW and a total transmission exceeding 66%.

Unique photoaffinity probes to study TGFß signaling and receptor fates.

A novel synthetic approach is used to prepare a diverse set of "first-in-class" dihydropyridine-based TGFß receptor degraders bearing photoaffinity labels. These probes serve as valuable tools to study TGFß receptor fates and dynamics - an important challenge in chemical biology.

Liquid human milk fortifier significantly improves docosahexaenoic and arachidonic acid status in preterm infants.

We report the fatty acid composition of mother׳s own human milk from one of the largest US cohorts of lactating mothers of preterm infants. Milk fatty acid data were used as a proxy for intake at enrollment in infants (n=150) who received human milk with a powder human milk fortifier (HMF; Control) or liquid HMF [LHMF; provided additional 12mg docosahexaenoic acid (DHA), 20mg arachidonic acid (ARA)/100mL human milk]. Mothers provided milk samples (n=129) and reported maternal DHA consumption (n=128). Infant blood samples were drawn at study completion (Study Day 28). Human milk and infant PPL fatty acids were analyzed using capillary column gas chromatography. DHA and ARA were within ranges previously published for US term and preterm human milk. Compared to Control HMF (providing no DHA or ARA), human milk fortified with LHMF significantly increased infant PPL DHA and ARA and improved preterm infant DHA and ARA status.

Metabolism and distribution of two highly potent and selective peptidomimetic inhibitors of matriptase.

Matriptase is a serine protease expressed by several types of cancer cells and it participates in tumour growth and progression through the activation of hepatocyte growth factor (HGF) and urokinase-type plasminogen activator (uPA). The metabolism of two potent and selective peptidomimetic inhibitors of matriptase (CJ-1737 and CJ-672) was examined in vitro with enzyme preparations (9000g supernatants, microsomes, and plasma) from dog, pig, rat, and human. It was found that both compounds displayed interesting species-dependent differences. Though CJ-1737 was not metabolized by microsomes, by 9000g supernatants from all species, or by human or rat plasma, canine and porcine plasma enzymes rapidly hydrolysed this compound. In contrast, CJ-672 was metabolized exclusively by enzymes from human liver (microsomes and 9000g supernatants) via a two-step metabolic pathway. Additionally, the distribution of both compounds was investigated in mice. The highest amounts were measured in the kidney and liver, followed by the spleen, lung, and heart. In contrast to CJ-1737, high concentrations of CJ-672 were detected in the colon, indicating an additional biliary excretion. In summary, this work clarifies both the metabolism and distribution of two new matriptase inhibitors and demonstrates important metabolic differences between human enzymes and those from commonly used laboratory animals.

Biochemical and white blood cell profiles of baboon neonates consuming formulas with moderate and high dietary long-chain polyunsaturated fatty acids.

BACKGROUND: Clinical chemistry and complete blood count (CBC) values were determined in 14 term baboons (Papio species) consuming formula with moderate or high levels of dietary long-chain polyunsaturated fatty acids (LCPUFA) from 2-12 weeks of age. METHOD: Neonates were randomized to three groups: C: Control, no LCPUFA; L: 0.33% docosahexaenoic acid (DHA)/0.67% arachidonic acid (ARA) (w/w); L3:1.00% DHA/0.67% ARA (w/w). Blood chemistries were assessed at 6 and 12 weeks and CBC parameters were measured at 2, 4, 8, 10, 12 weeks of age. RESULTS: Dietary LCPUFA had significant effects on serum triglyceride (C > L,L3) and calcium (L > C,L3). No other significant effects of diet were detected; pooled values are presented for all other parameters. CONCLUSION: These data provide longitudinal biochemical and white cell/platelet/immunological data on LCPUFA-fed baboons over the first 12 weeks of life. Data ranges are similar to reference data in cases for which values exist and hematological changes reflect trends observed during human neonatal development.

The development of a transformation system for the dimorphic plant pathogen Holleya sinecauda based on Ashbya gossypii DNA elements.

We have developed a transformation system for the dimorphic plant pathogenic fungus Holleya sinecauda based on an electroporation protocol used for the closely related filamentous fungus Ashbya gossypii. DNA-mediated transformation of the dominant selection marker kanMX generated H. sinecauda transformants that were resistant to the antibiotic drug G418/geneticin. Freely replicating plasmids could be established in H. sinecauda using an A. gossypii autonomously replicating sequence (ARS) element, whereas Saccharomyces cerevisiae ARS elements, which are functional in A. gossypii, were not functional in H. sinecauda. In addition, centromeric DNA of A. gossypii stabilized the maintenance of plasmids in H. sinecauda under non-selective conditions. We isolated a fragment of the HsLEU2 gene and used this locus for targeted integration of kanMX3, consisting of the kanMX gene flanked by direct repeats. This allowed the construction of a Hsleu2 strain which became G418 sensitive after direct repeat-induced marker excision. The Hsleu2 strain can be complemented by the ScLEU2 gene. Finally, we constructed high- and low-copy shuttle vectors for H. sinecauda.

Negligible changes in piglet serum clinical indicators or organ weights due to dietary single-cell long-chain polyunsaturated oils.

Single-cell oils are currently included in human infant formula as sources of the long-chain polyunsaturates (LCP) docosahexaenoic acid (DHA) and arachidonic acid (AA) in many countries, but have not yet been approved for use in the USA. We prepared four bovine-milk-based formulas with AA/DHA=0, 34/17, 68/34 and 170/85 (mg per 100 kcal formula) provided by two commercial single-cell oils. These levels correspond approximately to 0, 1, 2 and 5 times the concentrations used in infant formulas and, due to greater consumption of formula per unit body weight, resulted in daily consumption of approximately 0, 3, 6 and 16 times those anticipated for human infants. All other dietary fat (47% of calories) was provided by a vegetable oil blend used in commercial human infant formulas. Domestic piglets were allowed to nurse with the sow for 24 h after parturition, then removed to individual cages and maintained on one of the four diets. At 30 days of age the piglets were sacrificed, and serum collected and organs weighed. With litters treated as a blocked variable, no significant differences among groups were found by analysis of variance for the following serum assays: alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine, albumin, glucose, cholesterol, triglycerides, and total protein. No significant differences were found for hematocrit or body weight. No significant differences were found among groups for weights of liver, brain, heart, lung, spleen, kidneys or lung, analyzed as absolute weight and as a fraction of body weight. Hematoxylin/eosin liver sections examined by light microscopy showed no abnormalities as evaluated by an independent pathologist. DHA content in liver and heart and AA content in heart showed significant dose-related accumulation (P<0.05) and confirmed enhanced tissue accretion of DHA and AA from both oils. We conclude that single-cell oils in formula consumed for 1 month in amounts up to 16-fold greater than proposed for human infants in the USA did not result in clinical chemistry or histopathologic indications of toxic effects in neonatal pigs.

Ten pivotal questions about diabetic ketoacidosis. Answers that clarify new concepts in treatment.

Nearly all physicians have cared for patients with diabetic ketoacidosis sometime during their training or have encountered patients with hyperglycemia and ketonuria in their office practice. In the last decade, many studies have challenged the traditional concepts about diabetic ketoacidosis treatment, resulting in sometimes confusing recommendations. In this article, Drs Carroll and Schade answer 10 frequently asked questions about the diagnosis and treatment of diabetic ketoacidosis and discuss related hospitalization issues.

Effect of short-term glucose control on glycemic thresholds for epinephrine and hypoglycemic symptoms.

Hypoglycemia is the principal barrier to achieving target glucose goals in type 2 diabetes. The effect of short-term improvement in glycemic control on plasma glucose thresholds for symptomatic and hormonal responses to hypoglycemia in type 2 diabetes is not known. We hypothesized that the thresholds for these events would be increased by 1 wk of improved glycemic control in elderly patients with type 2 diabetes. Ten elderly patients with type 2 diabetes were admitted for an 8-d inpatient protocol. All subjects underwent insulin-induced hypoglycemia on days 2 (preglucose control) and 8 (postglucose control). Between days 2 and 8, subjects received intensive diabetes management to improve their glycemic control. Timed blood glucose profiles were obtained daily during the week before and during admission. Plasma glucose, counterregulatory hormones, and hypoglycemic symptoms were assessed at baseline and every 10 min during the hypoglycemic studies. Mean blood glucose concentrations were significantly reduced by intensive diabetes management from 9.8 +/- 3.7 mmol/liter to 7.7 +/- 3.3 mmol/liter (P < 0.001). The plasma glucose threshold for epinephrine release during insulin-induced hypoglycemia was significantly increased by intensive management from a glucose concentration of 3.7 +/- 0.5 mmol/liter at baseline to 3.1 +/- 0.3 mmol/liter after intensive management (P < 0.05). The plasma glucose threshold for hypoglycemic symptoms was also increased by intensive therapy from a glucose concentration of 5.3 +/- 1.2 to 3.3 +/- 0.6 mmol/liter (P = 0.003). These rapid changes may increase the risk for severe hypoglycemia in type 2 diabetes and limit the ability of physicians to rapidly correct hyperglycemia in elderly type 2 diabetes patients.

A biethnic community survey of cognition in participants with type 2 diabetes, impaired glucose tolerance, and normal glucose tolerance: the New Mexico Elder Health Survey.

OBJECTIVE: To determine whether elderly individuals with type 2 diabetes or impaired glucose tolerance are at increased risk for cognitive impairment compared with individuals with normal glucose tolerance. RESEARCH DESIGN AND METHODS: Elderly Hispanic individuals (n = 414) and non-Hispanic white individuals (n = 469) aged > or =65 years, randomly selected from the Medicare rolls of Bernalillo County (Albuquerque), NM, were recruited for an interview/examination that included an evaluation of glucose tolerance. Information on nine tests of cognitive function and two measures of depression allowed comparisons between diabetic status and these functions. Comparisons also were made between glycosolated hemoglobin concentrations and these cognitive tests in the 188 participants with diabetes. RESULTS: None of the mean scores on the tests of cognitive function was significantly lower in the participants with diabetes compared with those participants with normal glucose tolerance after adjustments for ethnicity, sex, age, level of education, and presence of depression, with or without elimination of those with dementia (Mini-Mental State Exam <18). Interestingly, participants with impaired glucose tolerance tended to score higher than those with normal glucose tolerance. No significant associations were found between glycosolated hemoglobin concentrations and cognitive test scores in participants with diabetes. CONCLUSIONS: We could not show any increased risk for cognitive impairment in participants with diabetes compared with those with normal glucose tolerance after adjustments for ethnicity, sex, age, education, and presence of depression, before or after elimination of dementia in this random sample from a biethnic population of predominantly community-dwelling elders.

Differential effects of fasting and dehydration in the pathogenesis of diabetic ketoacidosis.

Glycemia varies widely in patients with diabetic ketoacidosis (DKA), with plasma glucose concentrations between 10 to 50 mmol/L commonly encountered. The mechanism of this glycemic variability is uncertain. Our study examined the differential effects of fasting and dehydration on hyperglycemia induced by withdrawal of insulin in type 1 diabetes. To evaluate the respective roles of dehydration and fasting in the pathogenesis of DKA, 25 subjects with type 1 diabetes were studied during 5 hours of insulin withdrawal before (control) and after either 32 hours of fasting (n = 10) or dehydration of 4.1% +/- 2.0% of baseline body weight (n = 15). Samples were obtained every 30 minutes during insulin withdrawal for substrate and counterregulatory hormone levels and rates of glucose production and disposal. Fasting resulted in reduced plasma glucose concentrations compared with the control study, while dehydration resulted in increased plasma glucose concentrations compared with the control study (P < .001). Glucose production and disposal were decreased during the fasting study and increased during the dehydration study compared with the control study. Glucagon concentrations and rates of development of ketosis and metabolic acidosis were increased during both fasting and dehydration compared with control. These data suggest that fasting and dehydration have differential effects on glycemia during insulin deficiency, with dehydration favoring the development of hyperglycemia and fasting resulting in reduced glucose concentrations. This finding is probably attributable to the differing effect of these conditions on endogenous glucose production, as well as to differences in substrate availability and counterregulatory hormone concentrations. The severity of pre-existing fasting and dehydration likely explains much of the variability in plasma glucose concentrations observed in DKA.

Low-dose epinephrine supports plasma glucose in fasted elderly patients with type 2 diabetes.

Recent studies indicate that endogenous epinephrine provides protection against hypoglycemia in fasted elderly patients with type 2 diabetes treated with sulfonylureas. To establish a dose-response relationship and further characterize this hormonal action, 10 subjects with type 2 diabetes aged 67 +/- 1.3 years and receiving glyburide 20 mg daily were studied on 3 separate occasions. Saline placebo, half dose epinephrine ([Epi] 0.375 microg/min), and full dose Epi (0.75 microg/min) were infused during the final 10 hours of a 28-hour fast in a paired, randomized single-blind study to simulate physiologic epinephrine levels. Substrate and hormonal parameters and glucose production (Rd), disposal (Rd), and metabolic clearance rates were determined every 30 minutes. In the placebo study, the mean decline in plasma glucose during the final 10 hours of fasting was -2.7 +/- 0.6 mmol/L, compared with -0.3 +/- 0.3 mmol/L in the half dose Epi study and an actual increase in glucose of 1.0 +/- 0.8 mmol/L in the full dose Epi study (P < .001). There was a similar decline in the glucose Ra in all 3 studies, and the glucose Rd was not significantly different among the 3 study conditions. The baseline-adjusted metabolic clearance rate of glucose was significantly decreased during the epinephrine studies compared with the placebo study (P = .01). The concentration of other counterregulatory hormones did not differ between the studies. We conclude that low physiologic concentrations of epinephrine prevent the progressive decline in plasma glucose observed during fasting in elderly sulfonylurea-treated patients with type 2 diabetes. This finding may be attributable to a relative insulin resistance induced by epinephrine, resulting in a decreased rate of glucose clearance by cells.

Potato-lactulose breath hydrogen testing as a function of gastric motility in diabetes mellitus.

OBJECTIVE: Scintigraphic determination of gastric emptying is the current standard for the assessment of gastric motility and the diagnosis of diabetic gastroparesis. However, such studies are expensive, inconvenient, and involve exposure to radiation. Because the time course of breath hydrogen (H2) excretion after ingestion of lactulose correlates with upper gastrointestinal transit time, we hypothesized that patients with diabetic gastroparesis would exhibit prolonged breath H2 excretion after ingestion of a test meal containing complex carbohydrate and lactulose compared to subjects without diabetes and subjects with diabetes but without gastroparesis. RESEARCH DESIGN AND METHODS: Ten healthy subjects without diabetes, 10 subjects with diabetes but without gastroparesis (gastric emptying T1/2,T1/2 < 90 minutes), and 10 subjects with diabetes and previously diagnosed gastroparesis (T1/2 > 90 minutes) were admitted for a single 24-hour study. Gastric motility agents were withheld 24 hours prior to the study. Euglycemia was established and maintained overnight in subjects with diabetes with continuous intravenous insulin infusion. At 6:00 AM, all subjects ingested a breakfast containing 100 g of cooked potato starch and 20 g lactulose. Breath H2 excretion was monitored at baseline and every 30 minutes for 12 hours after ingestion of the test meal. RESULTS: Twelve hours after ingestion of the test meal, raw and baseline adjusted breath H2 excretion was significantly elevated in the gastroparesis group compared to the unaffected group with diabetes and the group without diabetes (p < 0.001). The baseline and 12-hour data points were adequate to discriminate between normal and delayed gastric emptying. CONCLUSIONS: We conclude that patients with previously diagnosed gastroparesis exhibit prolonged breath H2 excretion after ingestion of a test meal. This test may prove to be a safe, reliable, and affordable outpatient screening test for diabetic gastroparesis.

What are the barriers to medical care for patients with newly diagnosed diabetes mellitus?

CONTEXT: Few data are available describing factors that prevent patients with newly diagnosed diabetes from seeking medical care. OBJECTIVE: To identify socioeconomic factors that act as barriers to healthcare among such patients. SETTING: A community-wide diabetes screening programme. PARTICIPANTS: One hundred and eighteen patients with newly identified diabetes mellitus out of 1,824 total screenings. INTERVENTIONS: Each newly identified person with diabetes was instructed to contact a physician for follow-up care. DESIGN: A follow-up survey was obtained from 89 (75%) subjects 9 +/- 7 months after diagnosis. MAIN OUTCOME MEASURE: Whether or not subjects had obtained follow-up care for their diabetes. RESULTS: Of seven variables examined, only lack of health insurance correctly predicted those patients who failed to seek medical care for their diabetes by multivariate analysis. CONCLUSIONS: Lack of health insurance coverage is the primary reason that patients with newly diagnosed diabetes fail to seek medical care.

Low-dose ethanol predisposes elderly fasted patients with type 2 diabetes to sulfonylurea-induced low blood glucose.

OBJECTIVE: It has previously been demonstrated that the risk of hypoglycemia is low among otherwise healthy elderly fasted patients with type 2 diabetes taking oral sulfonylurea medications. Nevertheless, these agents do cause hypoglycemia in clinical practice, suggesting that accompanying factors must typically be present for hypoglycemia to occur. Ethanol is one putative risk factor that has not been evaluated as a mechanism for low blood glucose among sulfonylurea users. We hypothesized that low concentrations of ethanol would reduce blood glucose concentrations in elderly type 2 diabetic patients receiving sulfonylureas during a short-term fast. RESEARCH DESIGN AND METHODS: A total of 10 type 2 diabetic patients, aged 68 +/- 3 years and receiving 20 mg glyburide daily, participated in a prospective double-blind placebo-controlled in-patient study consisting of two 24-h fasts at least 1 week apart. During hours 14 and 15 of the fasting studies, subjects received intravenous infusions of either 4.35 mmol.kg-1.h-1 ethanol (equivalent to one or two alcoholic beverages) or saline placebo in random order. Ethanol, plasma glucose, insulin, and counterregulatory hormones were assessed very 30-60 min during the final 10 h of the fast. RESULTS: Blood ethanol levels peaked at 17 +/- 2 mmol/l (the lower legal limit of intoxication in New Mexico) during the ethanol study. Plasma glucose concentrations did not differ at baseline (placebo 8.5 +/- 1.8 vs. ethanol 8.7 +/- 1.7 mmol/l; P = 0.50), but nadir plasma glucose was lower after the ethanol infusion compared with placebo (4.4 +/- 1.2 vs. 5.0 +/- 1.4 mmol/l; P = 0.01), and the absolute decline in plasma glucose was also greater during the ethanol study than the placebo study (4.7 +/- 0.9 vs. 3.6 +/- 1.2 mmol/l; P = 0.01). Counterregulatory hormone levels were increased during the ethanol study and nonesterified fatty acid concentrations were suppressed compared with the placebo study. CONCLUSIONS: Low doses of ethanol predispose fasted elderly type 2 diabetic patients to low blood glucose during a short-term fast. This may be one of several mechanisms by which sulfonylurea-induced hypoglycemia occurs in elderly patients.

Subclinical hypothyroidism in a biethnic, urban community.

OBJECTIVES: To evaluate the association between hypothyroidism, and the health status of older Hispanic and non-Hispanic white (NHW) men and women. To accomplish this, we determined the prevalences of the treated and untreated conditions and examined the associations between an elevated serum thyroid stimulating hormone (TSH) and cognitive and affective (mood) functions and the prevalences of symptoms and comorbidity, specifically coronary heart disease (CHD), diabetes, hypertension, and hyperlipidemia. DESIGN AND SETTING: A cross-sectional study of equal numbers of Hispanic and NHW men and women selected randomly from the Health Care Financing Administration (Medicare) rolls and recruited for a home interview followed by a 4-hour interview/examination in a senior health clinic. PARTICIPANTS: 883 volunteers, mean age 74.1 years, participated in interviews/examinations MEASUREMENTS: Serum TSH was determined in 825 participants responding to questions about thyroid replacement therapy. Serum free thyroxine (free T4) concentrations were determined in 139 participants with elevated TSH concentrations (>4.6 microU/mL). Symptoms, cognitive tests, a screen for depression, comorbidities (e.g., CHD), and risk factors (e.g., lipid abnormalities, diabetes, and hypertension) were compared in participants with high versus normal TSH values. RESULTS: Subclinical hypothyroidism is more common in women than in men and in non-Hispanic white women compared with Hispanic women. No differences were observed between participants with TSH elevations from 4.7 to 10 microU/mL and those with normal TSH concentrations, and only a few differences were observed in those with TSH concentrations above 10. CONCLUSIONS: Subclinical hypothyroidism is a common condition in community-living older people, especially women. However, it appeared to have no effect on any of the measures of health status utilized until serum TSH concentrations exceeded 10 microU/mL, and even then the effects were rarely significant.

Optimal administration of lispro insulin in hyperglycemic type 1 diabetes.

OBJECTIVE: Lispro is a new rapidly absorbed insulin analog. At present, there are no recommendations for the optimal injection time of lispro insulin in hyperglycemic patients. In contrast to normoglycemic patients with diabetes, we hypothesized that injection of lispro insulin 15-30 min before meal ingestion would improve postprandial glucose excursion in hyperglycemic diabetic subjects. RESEARCH DESIGN AND METHODS: In 48 randomized overnight studies, 12 healthy adult type 1 diabetic patients received lispro insulin 0.15 U/kg admixed with human ultralente 0.2 U/kg (as background insulin) subcutaneously at minutes (-30, -15, 0, and +15) relative to the ingestion of an American Diabetes Association breakfast of 8.6 kcal/kg. Pre-breakfast hyperglycemia of 10.2 +/- 0.2 mmol/l was established before the study by continuous overnight infusion of intravenous insulin, which was stopped 30 min before lispro insulin injection. Glucose and insulin levels were measured every 30 min for 5 h after breakfast. RESULTS: Results demonstrated that postprandial glucose excursion was reduced when lispro insulin was administered 15 or 30 min before the meal compared with lispro insulin injected at the meal (P < 0.002). The postprandial glucose excursion (millimoles per liter per hour) was -6.4 +/- 3 for the -30-min group, -5.1 +/- 2.9 for the -15-min group, 3.4 +/- 4.1 for the 0-min group, and 5.7 +/- 4.4 for the +15-min group. Although injecting lispro insulin at 30 min before the meal resulted in a significant reduction in postprandial glycemia, it was accompanied by loss of glucose control at 4 h postmeal in two subjects. CONCLUSIONS: Optimization of lispro insulin in hyperglycemic patients requires timing of the insulin injection at least 15 min before the meal.