Sub-second periodicity in a fast radio burst.

Fast radio bursts (FRBs) are millisecond-duration flashes of radio waves that are visible at distances of billions of light years1. The nature of their progenitors and their emission mechanism remain open astrophysical questions2. Here we report the detection of the multicomponent FRB 20191221A and the identification of a periodic separation of 216.8(1) ms between its components, with a significance of 6.5σ. The long (roughly 3 s) duration and nine or more components forming the pulse profile make this source an outlier in the FRB population. Such short periodicity provides strong evidence for a neutron-star origin of the event. Moreover, our detection favours emission arising from the neutron-star magnetosphere3,4, as opposed to emission regions located further away from the star, as predicted by some models5.

A repeating fast radio burst source localized to a nearby spiral galaxy.

Fast radio bursts (FRBs) are brief, bright, extragalactic radio flashes1,2. Their physical origin remains unknown, but dozens of possible models have been postulated3. Some FRB sources exhibit repeat bursts4-7. Although over a hundred FRB sources have been discovered8, only four have been localized and associated with a host galaxy9-12, and just one of these four is known to emit repeating FRBs9. The properties of the host galaxies, and the local environments of FRBs, could provide important clues about their physical origins. The first known repeating FRB, however, was localized to a low-metallicity, irregular dwarf galaxy, and the apparently non-repeating sources were localized to higher-metallicity, massive elliptical or star-forming galaxies, suggesting that perhaps the repeating and apparently non-repeating sources could have distinct physical origins. Here we report the precise localization of a second repeating FRB source6, FRB 180916.J0158+65, to a star-forming region in a nearby (redshift 0.0337 ± 0.0002) massive spiral galaxy, whose properties and proximity distinguish it from all known hosts. The lack of both a comparably luminous persistent radio counterpart and a high Faraday rotation measure6 further distinguish the local environment of FRB 180916.J0158+65 from that of the single previously localized repeating FRB source, FRB 121102. This suggests that repeating FRBs may have a wide range of luminosities, and originate from diverse host galaxies and local environments.

De novo HLA sensitization and antibody mediated rejection following pregnancy in a heart transplant recipient.

Here we report a case wherein both donor-specific and third-party, paternal, HLA class II specific antibodies developed following a spontaneous miscarriage resulting in antibody-mediated rejection in a patient who had undergone an orthotopic cardiac transplant six years earlier.

Absence of microorganisms in crustacean digestive tracts.

Two marine and one terrestrial wood-boring isopod species and one wood-inhabiting amphipod species maintain a digestive tract free of microorganisms. Digestive tracts examined in toto with the scanning electron microscope were devoid of microorganisms. In contrast, the outer exoskeleton surfaces of these crustaceans support a dense bacterialflora. Observations of the hindgut of termites revealed a diverse gut microflora as expected.

Does occupational success influence longevity among England test cricketers?

OBJECTIVE: To determine whether the longevity of England test cricketers is influenced by occupational success, controlling for the influence of social background. DESIGN: Archival survey. SETTING: England. SUBJECTS: Those 418 cricketers who played for England in a test match from the first test in 1876 to 1963 when the distinction between amateur and professional status was removed. MAIN OUTCOME MEASURES: Length of life. RESULTS: Survival analysis of players born between 1827 and 1941 (349 dead, 69 alive) showed a significant relation between mortality and year of birth (p<0.001), amateur/professional status (p = 0.042) and the number of test matches played (p = 0.042). Captaining England was not related to survival. CONCLUSION: The link between longevity and both social background and occupational success is supported among test match cricketers. Amateur (or "gentlemen") cricketers from more privileged social backgrounds survived longer than professionals (or "players"). The most successful cricketers who played in a larger number of tests lived longer than those who played in a smaller number of tests. Captaining England, which could be regarded as a form of occupational "control", was not associated with longevity.

Direct muscarinic cholinergic inhibition of hepatic glucose production in humans.

To explore the potential role of the parasympathetic nervous system in human glucoregulatory physiology, responses to the muscarinic cholinergic agonist bethanechol (5.0 mg s.c.) and antagonist atropine (1.0 mg i.v.) were measured in normal humans. There were no changes in the plasma glucose concentration or rates of glucose production or utilization following atropine administration. After bethanechol administration there were no changes in the plasma glucose concentration or fluxes despite increments in plasma glucagon (75 +/- 7 to 103 +/- 10 pg/ml, P less than 0.02). There were no changes in insulin or C-peptide levels. To test the hypothesis that direct muscarinic inhibition of glucose production was offset by an indirect action of the agonist, specifically increased glucagon secretion with consequent stimulation of glucose production, bethanechol was administered while glucagon levels were held constant with the islet clamp technique (somatostatin infusion with insulin, glucagon and growth hormone replacement at fixed rates). Under that condition the muscarinic agonist induced a 25% decrement in the plasma glucose concentration (101 +/- 8 to 75 +/- 8 mg/dl, P less than 0.05). When compared with separate clamp control studies (with placebo rather than bethanechol injection) both the rate of glucose production and the glucose concentration were reduced (P less than 0.05) following bethanechol injection; the rate of glucose utilization was unaltered. Thus, we conclude: Withdrawal of parasympathetic tone does not appear to be an important glucoregulatory process in humans. Direct muscarinic cholinergic inhibition of hepatic glucose production occurs in humans but during generalized muscarinic activation this is offset by an indirect muscarinic action, increased glucagon secretion with consequent stimulation of glucose production. Thus, particularly if regional neuronal firing occurs, the parasympathetic nervous system may play an important role in human glucoregulatory physiology.

Diminished brain glucose metabolism is a significant determinant for falling rates of systemic glucose utilization during sleep in normal humans.

Systemic glucose utilization declines during sleep in man. We tested the hypothesis that this decline in utilization is largely accounted for by reduced brain glucose metabolism. 10 normal subjects underwent internal jugular and radial artery cannulation to determine cerebral blood flow by N2O equilibrium technique and to quantitate cross-brain glucose and oxygen differences before and every 3 h during sleep. Sleep stage was graded by continuous electroencephalogram, and systemic glucose turnover was estimated by isotope dilution. Brain glucose metabolism fell from 33.6 +/- 2.2 mumol/100 g per min (mean +/- SE) before sleep (2300 h) to a mean nadir of 24.3 +/- 1.1 mumol/100 g per min at 0300 h during sleep (P = 0.001). Corresponding rates of systemic glucose utilization fell from 13.2 +/- 0.8 to 11.0 +/- 0.5 mumol/kg per min (P = 0.003). Diminished brain glucose metabolism was the product of a reduced arteriovenous glucose difference, 0.643 +/- 0.024 to 0.546 +/- 0.020 mmol/liter (P = 0.002), and cerebral blood flow, 50.3 +/- 2.8 to 44.6 +/- 1.4 cc/100 g per min (P = 0.021). Brain oxygen metabolism fell commensurately from 153.4 +/- 11.8 to 128.0 +/- 8.4 mumol/100 g per min (P = 0.045). The observed reduction in brain metabolism occurred independent of stage of central nervous system electrical activity (electroencephalographic data), and was more closely linked to duration of sleep. We conclude that a decline in brain glucose metabolism is a significant determinant of falling rates of systemic glucose utilization during sleep.

Smoking compromises cause-specific survival in patients with operable colorectal cancer.

AIMS: To assess whether active smoking compromises survival in patients with colorectal cancer. MATERIALS AND METHODS: We studied a regionally based cohort of 284 consecutive patients referred to the Tayside Cancer Centre for consideration of adjuvant treatment after curative surgery for colorectal cancer. RESULTS: Cause-specific survival was significantly worse (P = 0.0015) in patients who were actively smoking at the time of their first post-operative visit. The absolute difference in 5-year cause-specific survival (active smokers vs the rest) was 21%. In adjusted multi-variate analysis of patients after pathologically complete (R0) resection, the hazard ratio was 2.55 (95% confidence interval 1.40-4.64) in active smokers compared with non-smokers. T stage, number of positive nodes and co-morbidity score were also of independent prognostic influence. CONCLUSIONS: Persistent smoking was, in this small series, an important and independent predictor of cancer-related death after surgery for cancer of the large bowel. Because smoking and deprivation are related, some of the adverse effects of deprivation upon survival in this group of patients may be explained by smoking behaviour.

The rational for a mid-scala electrode array.

Today increasing numbers of cochlear implant candidates have residual hearing that can be aided and hence is worth trying to preserve. This means that surgical technique and electrode array design must be adapted to minimize trauma. Wide opening of the round window is often preferred to reduce drill related trauma and to avoid pressure spikes during electrode array insertion. A recent meta-analysis suggested that there is no significant correlation between hearing preservation and either insertion depth or scala position. However, a slow insertion speed of at least 30seconds was associated with better hearing preservation. An electrode design is proposed that targets the middle of the scala tympani. This minimizes frictional forces from either lateral or medial wall during insertion and imposes less static pressure on cochlear structures following insertion. The flexibility to insert via the round window requires a 0.7-mm maximum dimension at the proximal end of the array. Micro-anatomical analysis by micro-CT indicated that a 420-degree insertion depth was optimal between cochlear coverage and available space within the scala tympani. Physical measurements showed that mean insertion forces remained below 10mN during insertion. A series of 20 human temporal bone insertions found a mean insertion depth of 400 degrees with no scala dislocations. Six clinical series, in total 94 cases, found postoperative hearing in 81% of cases with a mean loss of 12dB compared to preoperative levels. Speech understanding out to one year post-fitting trended better for a mid-scala design group than for a straight electrode array group; although the differences were not statistically significant. A mid-scala array design appears able to be inserted with minimal trauma, to return a predictable insertion depth across various sizes of cochleae and to support reasonable levels of speech understanding without relying on residual hearing.

Higher glycemic thresholds for symptoms during beta-adrenergic blockade in IDDM.

We tested the hypotheses that nonselective beta-adrenergic blockade does not cause absolute hypoglycemia unawareness but shifts the glycemic thresholds for symptoms to lower plasma glucose concentrations and that neither neuroglycopenic symptoms nor cognitive impairments during hypoglycemia are altered by beta-adrenergic blockade. To do so, we applied the euglycemic and stepped hypoglycemic clamp techniques to patients with moderately controlled insulin-dependent diabetes mellitus (IDDM) in the absence (n = 8) and presence (n = 9) of the nonselective beta-adrenergic antagonist propranolol. Compared with the corresponding euglycemic clamps, total symptom scores first increased at the 4.4-mM plasma glucose step (a higher level than that of 2.8 mM in nondiabetic subjects studied previously) in the absence of propranolol. Beta-adrenergic blockade did not produce absolute hypoglycemia unawareness. Indeed, at the frankly hypoglycemic step of 2.8 mM, total symptom scores tended to be higher in the presence than in the absence of propranolol. This was largely the result of greater (P less than 0.01) perception of diaphoresis. However, symptom scores did not increase until the 3.3-mM plasma glucose step during beta-adrenergic blockade. The perception of hunger, and perhaps that of tremulousness, was reduced by propranolol at the higher glucose steps. Neuroglycopenic symptoms were not reduced by propranolol. The cognitive function of memory, but not that of attention, was impaired, also starting at the 4.4-mM glucose step. This was not impaired further by propranolol. Thus, we formed the following conclusions. 1) Nonselective beta-adrenergic blockade does not cause absolute hypoglycemia unawareness but shifts the glycemic thresholds for symptoms to lower plasma glucose concentrations in patients with IDDM. 2) Beta-adrenergic blockade does not reduce neuroglycopenic symptoms, and it does not further impair cognitive function during hypoglycemia in IDDM patients.

Successful treatment of severe refractory sulfonylurea-induced hypoglycemia with octreotide.

OBJECTIVE: To test the clinical use of octreotide in the treatment of sulfonylurea-induced hypoglycemia. RESEARCH DESIGN AND METHODS: A case is reported of sulfonylurea-induced hypoglycemic coma in a nondiabetic subject, which was complicated by relapse of hypoglycemia after resuscitation with intravenous dextrose. Subcutaneous octreotide, 50 micrograms 12 hourly, suppressed stimulated endogenous insulin secretion, thereby preventing a further recurrence of hypoglycemia. RESULTS: No adverse effects of treatment were observed. CONCLUSIONS: These results suggest a significant role for octreotide as an adjunct to intravenous dextrose in the management of severe and refractory cases of sulfonylurea-induced hypoglycemia.

A treatable cause of recurrent severe hypoglycemia.

OBJECTIVE: To see if glucocorticoid deficiency might explain increased insulin sensitivity causing severe brittle diabetes in two type I diabetic patients. CASES: We describe two patients who developed brittle diabetes characterized by recurrent severe hypoglycemia on small daily insulin doses with severe hyperglycemia on further insulin dose reduction. In both patients, insulin requirements had fallen markedly. RESULTS: Both patients were found to have glucocorticoid deficiency. In one patient, this was a result of hypopituitarism, in which hypoglycemia was aggravated by growth hormone deficiency. In the other patient, glucocorticoid deficiency was the result of primary adrenal failure. Resolution of brittle diabetes and restoration of normal insulin doses followed steroid replacement therapy in both patients. CONCLUSIONS: These patients emphasize the importance of seeking an organic cause for recurrent severe hypoglycemia. Increasing insulin sensitivity in type I diabetic patients should alert clinicians to the possibility of glucocorticoid deficiency.

Octreotide reverses hyperinsulinemia and prevents hypoglycemia induced by sulfonylurea overdoses.

Emergency therapy of sulfonylurea overdoses with glucose is often unsatisfactory because glucose stimulates insulin release and initiates a need for escalating quantities of hypertonic glucose to maintain normoglycemia. We tested the hypothesis that octreotide, an analog of somatostatin, would reverse hyperinsulinemia induced by a sulfonylurea overdose. Eight normal subjects received glipizide (1.45 mg/kg) on three occasions. Within 3 h, all subjects became hypoglycemic (< 50 mg/dL) and were initially treated with 50% dextrose followed by 1) dextrose infusion, 2) octreotide (30 ng/kg.min, iv), or 3) diazoxide (300 mg, iv, every 4 h). Euglycemia (85 mg/dL) was maintained with supplementary dextrose in treatment limbs 2 and 3. Insulin concentrations were 4-5 times greater with dextrose alone or in combination with diazoxide than with octreotide (P < 0.01). Dextrose requirements during diazoxide or dextrose alone were not different, but were both greater than those during octreotide treatment (P < 0.0001). All therapies were stopped at 13 h. Glucose levels remained above 3.6 mmol/L (65 mg/dL) in six of eight subjects receiving octreotide for the remaining 4 h. Glucose fell to below 3.6 mmol/L within 1.5 h of stopping either dextrose or diazoxide in each subject. Overall, octreotide reduced and in four of eight subjects entirely eliminated the need for exogenous glucose after a large overdose of glipizide. We conclude that octreotide is safe and effective and should be strongly considered as a logical therapeutic alternative for this metabolic emergency.

Anthropometric, metabolic, and immunological effects of recombinant human growth hormone in AIDS and AIDS-related complex.

Metabolic and anthropometric changes induced by "pharmacological" versus "physiological" doses (5.0 vs. 2.5 mg, every other day) of recombinant human growth hormone (rhGH) were compared in 10 human immunodeficiency virus-positive patients with AIDS or AIDS-related complex. Five patients were randomly assigned to each treatment schedule in a 3-month prospective, double-blind clinical trial. Three of the 10 patients, none taking zidovudine and all with low initial CD4 counts, were withdrawn during the study due to acute opportunistic infections. During treatment, insulin-like growth factor-1 (IGF-1) levels increased significantly (p < 0.05) in the pharmacological hGH treatment group, whereas no significant change was observed in IGF-1 in the physiological dose rhGH group. In the pharmacological hGH treatment group, weight loss preceding the study was reversed (p < 0.05) in each of the four patients who completed the study. This weight gain was associated with increases (p < 0.05) in lean body mass and total body water, with concomitant decreases in fat mass (p < 0.05) and urinary nitrogen excretion. Muscle power and endurance, as assessed by standardized omnikinetic dynamometry, also improved. All four patients lost weight again (p < 0.05) 6 weeks after completion of the study and termination of rhGH treatment. Minor positive changes in body composition were also observed in the physiologic-dose hGH group. The pharmacological dose of hGH was associated with minor increments (p < 0.05) in fasting plasma glucose, insulin, and C-peptide concentrations, which were of negligible clinical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Results of our first nine intraportal islet allografts in type 1, insulin-dependent diabetic patients.

With the first demonstration of insulin independence following intraportal islet transplantation into a patient with type 1 diabetes, a new era of clinical islet transplantation will begin. This report provides our initial experience of clinical islet transplantation with a total of nine consecutive portal vein islet transplants in seven diabetic recipients. The first three transplants were done in nonrenal failure diabetics (NRFI) using 6319 +/- 2173 islets/kg body weight with islets processed from single pancreas and cultured for 7 days at 24 degrees C. Prednisone, azathioprine, and cyclosporine were initiated prior to transplant. While all three recipients demonstrated C-peptide function posttransplant, all three rejected their grafts at 2 weeks. Five days of OKT3 treatment failed to recover more than 10% of their rejecting islet grafts. The studies were then shifted to established kidney transplant recipients (EKI) maintaining their basal immunosuppression while adding 7 days of Minnesota antilymphoblast globulin (MALG) to the recipient using islets from single donor pancreas that had been cultured for 7 days at 24 degrees C. There were an average of 6161 +/- 911 islets transplanted intraportally into three EKI recipients. All three had C-peptide response from the transplant, but none achieved insulin independence. While the first patient rejected his graft at 2 weeks, two recipients demonstrated long-term islet function up to 10 months posttransplant. Sustacal challenge testing demonstrated C-peptide responsiveness, but in a delayed pattern suggesting insufficient islet mass had been transplanted. The next three kidney transplant recipients received islets from more than one donor pancreas averaging 13,916 +/- 556 islets/kg body weight. The first of these was the first to achieve insulin independence from 10 to day 25 posttransplant when she appeared to have a rejection episode. The second and third recipients were retransplanted with islets from multiple donors having achieved partial islet function from single pancreas donor. The first patient on triple immunosuppression is demonstrating long-term partial function at 184 days but is not insulin independent. The third patient on prednisone and azathioprine received one half his islets after 7-day culture and the other half after 7-day culture combined with cryopreservation. He is continuing to demonstrate insulin independence for 154 days post-transplant with a glycated hemoglobin value of 5.6%. Sustacal challenge data demonstrate a total stimulated C-peptide response of 155 rhomol/ml at 4 months post-transplant compared with 148 +/- 12 rhomol/ml for normal controls (NC) and 425 rhomol/ml for nondiabetic, established kidney transplant recipients on triple immunosuppression.(ABSTRACT TRUNCATED AT 400 WORDS)

Hypoglycemia. Pathophysiology and treatment.

Hypoglycemia is a common consequence of many diabetes treatments. As is true for many therapies for diseases with major pathologic consequences, the benefits and risks of treatment must be balanced. In intensified diabetes management, hypoglycemia is not an insurmountable problem but is unfortunately inevitable using the methods of glucose control currently available. Patients with type 1 diabetes seem to be at greater risk than patients with type 2 disease. The health care team must strive to help the patient maintain normoglycemia. The results of the DCCT and the United Kingdom Prospective Diabetes Study prove that near normoglycemia is clearly in the patient's best interest. Patient education has become focused on minimizing hyperglycemia; counseling on the dangers of hypoglycemia has not been given the same stature. Emphasis must be placed on minimizing even minor subclinical hypoglycemia because it will contribute to a vicious cycle of hypoglycemia begetting hypoglycemia.

Prevalence and correlates of snoring and observed apneas in 5,201 older adults.

The objectives of this study were to describe the prevalence of snoring, observed apneas, and daytime sleepiness in older men and women, and to describe the relationships of these sleep disturbances to health status and cardiovascular diseases (CVD). A cross-sectional design was employed to study sleep problems, CVD, general health, psychosocial factors, and medication use. The subjects were participants in the Cardiovascular Health Study, which included 5,201 adults, aged 65 and older, who were recruited from a random sample of Medicare enrollees in four U.S. communities. Study measures employed were sleep questions, echocardiography, carotid ultrasound, resting electrocardiogram, cognitive function, cardiopulmonary symptoms and diseases, depression, independent activities of daily living (IADLs), and benzodiazepine use. Thirty-three percent of the men and 19% of the women reported loud snoring, which was less frequent in those over age 75. Snoring was positively associated with younger age, marital status, and alcohol use in men, and obesity, diabetes, and arthritis in women. Snoring was not associated, however, with cardiovascular risk factors or clinical CVD in men or women. Observed apneas were reported much less frequently (13% of men and 4% women) than snoring, and they were associated with alcohol use, chronic bronchitis, and marital status in men. Observed apneas were associated with depression and diabetes in women. In both men and women, daytime sleepiness was associated with poor health, advanced age, and IADL limitations. The conclusions of the study were that loud snoring, observed apneas, and daytime sleepiness are not associated cross-sectionally with hypertension or prevalent CVD in elderly persons.

Spirometry and maximal respiratory pressure references from healthy Minnesota 65- to 85-year-old women and men.

OBJECTIVE: To obtain spirometry and maximal respiratory pressure (MRP) reference values for elderly persons. DESIGN: Survey. SETTING: General community. PARTICIPANTS: Four hundred seventy-one healthy ambulatory white women and men age 65+ years. METHODS: A stringent spirometry quality assurance program exceeded American Thoracic Society recommendations. A "healthy" subgroup of 176 women and 112 men between the ages of 65- and 85 years were identified by excluding those with conditions that negatively influenced FEV1 in a multiple regression analysis. Reference equations and normal ranges for FEV1, FVC, FEF25-75%, peak flow, and maximal inspiratory and expiratory pressures (MRPs) were determined from the healthy group with good quality maneuvers. RESULTS: Less than 10% of the subjects were unable to perform three acceptable spirometry maneuvers and ten MRP maneuvers. When the age and height corrected FEV1s from this group were compared with other spirometry reference studies, mean values from the women were nearly identical to those from Morris, while these men had substantially lower FEV1 values (by 0.3- to 0.5L) than elderly men in Crapo's study. Mean peak flow was over 20% higher when compared with previous studies, suggesting greater initial expiratory effort by our subjects. The maximal inspiratory pressure (MIP) values were about 20% higher than those reported by the Cardiovascular Health Study, perhaps because five MIP maneuvers were always performed. CONCLUSION: Spirometry and MRP reference values used for elderly patients should come from population studies using similar techniques and with large numbers of subjects over age 65 years.

Octreotide: a long-acting inhibitor of endogenous hormone secretion for human metabolic investigations.

Octreotide is a recently available, FDA-approved, long-acting analog of somatostatin. The efficacy and tolerability of octreotide were evaluated in a series of protocols in healthy volunteers to assess its suitability for use in clinical investigations involving short-term inhibition of endogenous hormone secretion. Prolonged (270 minutes) hyperglycemic clamps were used to assess octreotide-mediated suppression of glucose-stimulated endogenous insulin secretion. Compared with a saline-control infusion, octreotide (30 ng/kg/min) suppressed stimulated insulin (P < .0001) and C-peptide (P < .0001) concentrations to basal levels. During insulin-induced hypoglycemia (plasma glucose < 40 mg/dL), octreotide (30 ng/kg/min) effectively suppressed the secretion of glucagon (P < .05) and growth hormone (P < .0005). In islet cell clamp studies, octreotide (30 ng/kg/min) suppressed C-peptide (P < .001), glucagon (P < .01), and growth hormone concentrations to below basal (fasting) levels in all subjects. Subsequent infusion of exogenous insulin, glucagon, and growth hormone resulted in predictable and stable concentrations of each hormone during octreotide-mediated suppression of their endogenous secretion. Consistent with the long half-life of octreotide (approximately 90 minutes), the concentrations of all three hormones remained suppressed below basal levels throughout a 60-minute observation period following the termination of octreotide infusion. In separate high-dose octreotide infusion studies, octreotide (60 ng/kg/min) did not produce any apparent additional metabolic effects, but was associated with an unacceptable degree of gastrointestinal side effects.(ABSTRACT TRUNCATED AT 250 WORDS)