Nocturnal swallowing augments arousal intensity and arousal tachycardia.

Cortical arousal from sleep is associated with autonomic activation and acute increases in heart rate. Arousals vary considerably in their frequency, intensity/duration, and physiological effects. Sleep and arousability impact health acutely (daytime cognitive function) and long-term (cardiovascular outcomes). Yet factors that modify the arousal intensity and autonomic activity remain enigmatic. In this study of healthy human adults, we examined whether reflex airway defense mechanisms, specifically swallowing or glottic adduction, influenced cardiac autonomic activity and cortical arousal from sleep. We found, in all subjects, that swallows trigger rapid, robust, and patterned tachycardia conserved across wake, sleep, and arousal states. Tachycardia onset was temporally matched to glottic adduction-the first phase of swallow motor program. Multiple swallows increase the magnitude of tachycardia via temporal summation, and blood pressure increases as a function of the degree of tachycardia. During sleep, swallows were overwhelmingly associated with arousal. Critically, swallows were causally linked to the intense, prolonged cortical arousals and marked tachycardia. Arousal duration and tachycardia increased in parallel as a function of swallow incidence. Our findings suggest that cortical feedback and tachycardia are integrated responses of the swallow motor program. Our work highlights the functional influence of episodic, involuntary airway defense reflexes on sleep and vigilance and cardiovascular function in healthy individuals.

[Pathophysiology of obstructive sleep apnea]. / Pathophysiologie der obstruktiven Schlafapnoe.

The prevalence of obstructive sleep apnea (OSA) is considered to be very high in western industrialized countries. There are conservative and surgical forms of treatment for OSA; however, the pathophysiology is largely unexplained and cannot be explained by anatomical abnormalities alone. In recent years, a number of non-anatomical factors have been found that favor the development of OSA. These include the respiratory excitation threshold (arousals), the respiratory drive (loop gain), as well as the control and function of the muscular upper airway dilators. The understanding of the individual pathophysiological processes may be helpful in the future to develop individual treatment approaches for patients.

Physiological responses and perceived comfort to high-flow nasal cannula therapy in awake adults: effects of flow magnitude and temperature.

Clinical use of heated, high-flow nasal cannula (HFNC) for noninvasive respiratory support is increasing and may have a therapeutic role in stabilizing the upper airway in obstructive sleep apnea (OSA). However, physiological mechanisms by which HFNC therapy may improve upper airway function and effects of different temperature modes are unclear. Accordingly, this study aimed to determine effects of incremental flows and temperature modes (heated and nonheated) of HFNC on upper airway muscle activity (genioglossus), pharyngeal airway pressure, breathing parameters, and perceived comfort. Six participants (2 females, aged 35 ± 14 yr) were studied during wakefulness in the supine position and received HFNC at variable flows (0-60 L/min) during heated (37°C) and nonheated (21°C) modes. Breathing parameters via calibrated Respitrace inductance bands (chest and abdomen), upper airway pressures via airway transducers, and genioglossus muscle activity via intramuscular bipolar fine wire electrodes were measured. Comfort levels during HFNC were quantified using a visual analog scale. Increasing HFNC flows did not increase genioglossus muscle activation despite increased negative epiglottic pressure swings (P = 0.009). HFNC provided ∼7 cmH2O positive airway pressure at 60 L/min in nonheated and heated modes. In addition, increasing the magnitude of HFNC flow reduced breathing frequency (P = 0.045), increased expiratory time (P = 0.040), increased peak inspiratory flow (P = 0.002), and increased discomfort (P = 0.004). Greater discomfort occurred at higher flows in the nonheated versus the heated mode (P = 0.034). These findings provide novel insight into key physiological changes that occur with HFNC for respiratory support and indicate that the primary mechanism for improved upper airway stability is positive airway pressure, not increased pharyngeal muscle activity.NEW & NOTEWORTHY This study evaluated upper airway muscle function, breathing, and comfort across different HFNC flows and temperatures. There were no increases in genioglossus muscle activity at higher flows despite greater negative epiglottic pressure swings. Increasing negative pressure swings was associated with increasing discomfort in the nonheated mode. HFNC was associated with ∼7 cmH2O increase in positive airway pressure, which may be the primary mechanism for upper airway stability with HFNC rather than increases in pharyngeal muscle activity.

Mucopolysaccharidosis type IIID: 12 new patients and 15 novel mutations.

Mucopolysaccharidosis III D (Sanfilippo disease type D, MPS IIID) is a rare autosomal recessive lysosomal storage disorder previously described in only 20 patients. MPS IIID is caused by a deficiency of N-acetylglucosamine-6-sulphate sulphatase (GNS), one of the enzymes required for the degradation of heparan sulphate. So far only seven mutations in the GNS gene have been reported. The clinical phenotype of 12 new MPS IIID patients from 10 families was studied. Mutation analysis of GNS was performed in 16 patients (14 index cases). Clinical signs and symptoms of the MPS IIID patients appeared to be similar to previously described patients with MPS III. Early development was normal with onset of behavioral problems around the age of 4 years, followed by developmental stagnation, deterioration of verbal communication and subsequent deterioration of motor functions. Sequence analysis of the coding regions of the gene encoding GNS (GNS) resulted in the identification of 15 novel mutations: 3 missense mutations, 1 nonsense mutation, 4 splice site mutations, 3 frame shift mutations, 3 large deletions and 1 in-frame small deletion. They include the first missense mutations and a relatively high proportion of large rearrangements, which warrants the inclusion of quantitative techniques in routine mutation screening of the GNS gene.

Effects of pentobarbital on upper airway patency during sleep.

We hypothesised that pentobarbital would improve upper airway mechanics based on an increase in latency to arousal and amplitude of the phasic genioglossus electromyogram (EMG), and a decrease in the active upper airway critical closing pressure (P(crit)). 12 healthy subjects received pentobarbital (100 mg) or placebo in a double-blind, crossover protocol. During wakefulness, we measured the genioglossus reflex response to negative pressure pulses. During sleep, carbon dioxide was insufflated into the inspired air. Airway pressure was then decreased in a stepwise fashion until arousal from sleep. With basal breathing during sleep: flow rate was lower in volunteers given pentobarbital; end-tidal CO(2) concentration and upper airway resistance were greater; and P(crit) was unaffected (pentobarbital mean ± SD -11.7 ± 4.5 versus placebo -10.25 ± 3.6 cmH(2)O; p = 0.11). Pentobarbital increased the time to arousal (297 ± 63s versus 232 ± 67 s; p<0.05), at which time phasic genioglossus EMG was higher (6.2 ± 4.8% maximal versus 3.1 ± 3%; p<0.05) as were CO(2) levels. The increase in genioglossus EMG after CO(2) administration was greater after pentobarbital versus placebo. Pentobarbital did not affect the genioglossus negative-pressure reflex. Pentobarbital increases the time to arousal and stimulates genioglossus muscle activity, but it also increases upper airway resistance during sleep.

Rectal gas volume: Defining cut-offs for screening for evacuation disorders in patients with constipation.

BACKGROUND: Diagnosis of rectal evacuation disorders (RED) is currently based on anorectal manometry (ARM) and evacuation tests in specialized laboratories; we recently showed higher rectal gas volume (RGV) and maximum rectal gas transaxial area (MRGTA) measured on abdominal and pelvic computed tomography (CT) in patients with documented RED.The aim of this study was to obtain cut-off values of RGV, MRGTA, and rectal area on scout film (RASF) to differentiate constipated patients with RED from those without RED, based on ARM, balloon expulsion test (BET), and colon transit test. METHODS: We identified 118 constipated patients (65 with RED) with prior record of CT. Using standard CT software, we used a variable region of interest (ROI) program to measure RGV, MRTGA, and RASF, as previously described. We constructed receiver operating characteristics curves based on different values, and we estimated AUC, specificity, and positive predictive value (PPV) to detect RED in patients with constipation. KEY RESULTS: Receiver operating characteristics of the models to predict RED showed AUC 0.751 for RGV and 0.737 for MRGTA (both P<.001), and 0.623 for RASF (P=.029). At specificity of 90%, RGV of 30 mL had a PPV 77.3%, MRGTA of 10 cm2 had a PPV 75.0%, and RFAS of 9 cm2 had a PPV of 68.8% for identifying constipated patients with RED. CONCLUSIONS & INFERENCES: Rectal gas measurements on abdominal imaging may indicate RED in patients with constipation. At ~90% specificity for RED, RGV of 20 or 30 mL or MRGTA of 10 cm2 on CT has PPV ~75%, and RASF of >9 cm2 has PPV of ~69%.

Crystal structure of GCN4-pIQI, a trimeric coiled coil with buried polar residues.

Coiled coils consist of two or more alpha-helices wrapped around each other with a superhelical twist. The interfaces between helices of a coiled coil are formed by hydrophobic amino acid residues packed in a "knobs-into-holes" arrangement. Most naturally occurring coiled coils, however, also contain buried polar residues, as do the cores of the majority of naturally occurring globular proteins. Two common buried polar residues in both dimeric and trimeric coiled coils are asparagine and glutamine. In dimeric coiled coils, buried asparagine, but not glutamine, residues have been shown to confer specificity of oligomerization. We have placed a glutamine residue in the otherwise hydrophobic interior of a stable trimeric coiled coil, GCN4-pII, to study the effect of this buried polar residue in a trimeric coiled-coil environment. The resulting peptide, GCN4-pIQI, is a discrete, trimeric coiled coil with a lower stability than GCN4-pII. The crystal structure determined to 1.8 A shows that GCN4-pIQI is a trimeric coiled coil with a chloride ion coordinated by one buried glutamine residue from each monomer.

Indications for alcohol or bland soap in removal of aerobic gram-negative skin bacteria: assessment by a novel method.

A patient contact model was devised for health care workers (HCWs) to define heavy hand contamination with aerobic gram-negative bacilli (AGNB) that requires alcohol for complete removal. In patients, AGNB quantitation was per ml cup scrub fluid; in HCWs per ml glove juice. Following 15-second contact, two Proteeae groin carriers yielding greater than or equal to 4 log10 AGNB (high burden) transmitted greater than or equal to 3 log10 in 67% of 24 tests of six HCWs, and less than or equal to 2 log10 in 29%. Two carriers yielding less than or equal to 3 log10 in 38%. At less than or equal to 2 log10 HCW acquisitions, soap eliminated all AGNB in three of 10; alcohol in eight of eight (p = 0.009). Contact with densely colonized patient skin may cause heavy AGNB contamination of HCWs' hands that generally necessitates alcohol for complete removal.

Proteeae groin skin carriage in ambulatory geriatric outpatients.

Aerobic gram-negative bacillus (AGNB) groin skin carriage was prospectively studied in ambulatory geriatric outpatients: 42 from three nursing homes and 44 from private homes. Initially, 12 (28.6%) Proteeae carriers were in the former group and 3 (6.8%) were in the latter (P = 0.01). At one year, 6 of 7 surviving nursing home carriers remained Proteeae carriers while none from private homes remained carriers (P = 0.007). The annual prevalence of Proteeae carriage was 14 (33.3%) in nursing homes and 4 (9.1%) in private homes (P = 0.008); of non-Proteeae AGNB carriage, the annuyal prevalence was 2 (4.8%) and 4 (11.4%), respectively. Nursing home subjects had similar initial health characteristics; however, by one year, 5 of 12 carriers in contrast to 3 of 30 noncarriers were dead of chronic disease (P = 0.03). These nursing homes included persons with chronic diseases that apparently facilitated Proteeae carriage. Urethral catheters, skin ulcers, and recent antibiotics were not factors.

Proteeae groin skin carriage among nursing home residents--resistance to antiseptics.

Proteeae carriage was evaluated in groin skin carriers following vigorous antiseptic application. Three Proteus mirabilis carriers were treated with 60% isopropyl alcohol or 4% chlorhexidine, observed to prevent skin contact, and then recultured; at four and eight hours P mirabilis numbers remained undiminished. Ten Proteeae carriers received a series of nine body baths with soap, chlorhexidine, and 0.75% povidone-iodine plus three cefazolin injections over 16 to 34 days; cumulative treatments failed to clear seven carriers. Within three months, all were again carriers. Proteeae carriers also had affinity for groin carriage of various aerobic gram-negative bacilli (AGNB) including cefazolin-resistant strains. In seven subjects, more than one AGNB species were recovered shortly after applying an antiseptic. Proteeae groin skin carriage appears to reflect a major change in the nature of resident bacteria on intact groin skin.

Antimicrobial monitoring and evaluation.

Effective antimicrobial use is an essential component of patient care. Drug use evaluation should include the prophylactic, therapeutic, and empiric use of antimicrobials. The infection control practitioner has the unique knowledge and skills in epidemiology to be effective in the monitoring and evaluation process. This review outlines a variety of techniques to monitor and evaluate trends in the use of antimicrobial agents in health care facilities. Methods related to antimicrobial monitoring and evaluation are summarized.

Susceptibility to varicella virus of certain adults in the southeastern United States.

The serologic status of 76 adults was determined to evaluate their immunity to the varicella virus. Previous reports indicate that 92% to 98% of the adult population develop this immunity. Our experience with nosocomial varicella infection in two hospital employees suggested that more adults in this subtropical region may be susceptible to varicella infection. Three (7.1%) adults with a definite history of varicella had a positive indirect fluorescent antibody (IFA) test. Twenty-eight (72%) of 39 employees without a history had a positive serology, a rate lower than previously reported (p less than 0.002). Twenty-nine (85%) of 34 other adults and 60 (79%) of the 76 adults tested had positive tests; these rates are also lower than reported (p = 0.003 and less than 0.001, respectively). These data indicate that some adult groups may be more susceptible to varicella infection and suggest that knowledge of immunity should be an important health concern in some hospitals.

Sporadic bacteremia complicating central venous catheter use in a community hospital: a model to predict frequency and aid in decision-making for initiation of investigation.

Sporadic bacteremia complicating single-lumen central venous catheter (CVC) use was prospectively recorded in a community hospital in 1981 and 1982. Sixty-four of 1258 (5.1%) patients had definite bacteremia. A nested case-control study was then undertaken to identify predictive risk factors. Fifteen statistically significant factors found in the 1981 cohort were tested in the 1982 cohort, and four remained significant for both years. Univariate and multiple logistic regression analysis on both years' findings, separately and together, identified two independently associated factors: diagnosed respiratory colonization/infection (p less than 0.0001) and serum albumin level (p less than 0.001). Based on these factors, an equation was developed to express the probability of bacteremia. Solving this equation provides an infection control practitioner with an expected rate of bacteremia that complicates CVC use and provides an aid for decision-making for investigation in the absence of clusters.

Isolation and identification of impurities in 4-acetyl-2-(2'-hydroxyethyl)5,6-bis(4-chlorophenyl)-2H-pyridazin-3-one, an antihypertensive agent.

Three trace impurities found in 4-acetyl-2-(2'-hydroxyethyl)-5,6-bis(4-chlorophenyl)-2H-pyridazin-3-one (II), a novel antihypertensive agent, were isolated by a combination of low-pressure liquid chromatography and preparative TLC. These impurities were identified as the formate ester of II, a pyridazinone having a 2-methyl rather than the 2'-hydroxyethyl substituent, and a bis(pyridazinonyl)methane analog. In addition, the product of O-alkylation rather than of N-alkylation of 4-acetyl-5,6-bis(4-chlorophenyl)-2H-pyridazin-3-one (I) with ethylene carbonate was detected by high-performance liquid chromatography. The biological activity of these four impurities was compared to that of II.

Tumor inhibitory agents from Vauquelinia corymbosa (Rosaceae).

The chloroform extract of Vauquelinia corymbosa Correa has shown activity against the P-388 lymphocytic leukemia test system. The constituents responsible for this activity were identified as uvaol, ursolic acid, and betulinic acid. Their identity was proven by melting point; mixed melting point; elemental analysis; IR, PMR, and mass spectra; and preparation of derivatives.

Detroit's avoidable mortality project: breast cancer control for inner-city women.

Mammography remains substantially under-used in low-income minority populations despite its well-established efficacy as a means of breast cancer control. The Metropolitan Detroit Avoidable Mortality Project is a 2-year controlled clinical trial of coordinated interventions which seek to improve the use of early breast cancer detection services at five clinical sites providing primary health care services to inner-city women. Baseline assessment for two of the five participating clinic populations demonstrated that only one-quarter of women who visited these clinics were referred for mammography in 1988, and only half of those who were referred were able to complete the procedure. Patient characteristics including age, marital status, ethnicity, and insurance status were not associated with use of mammography during the baseline period. Each of the project's intervention components is a cue to action: a physician prompt for mammography referral within the medical record of procedure-due women, a reminder postcard for scheduled appointments, and a telephone call to encourage rescheduling of missed appointments. The interventions are initiated by a computerized information management system in the existing network of health care services. The patient's out-of-pocket mammography expense has been eliminated in three of the five sites. Although their efficacy as individual interventions has been well established, a controlled trial of computer prompts to physicians, reduced expense for patients, and patient appointment reminders as an integrated system in inner-city medical care settings has not been previously described. We have implemented the prompting, facilitated rescheduling procedures, and eliminated patient expense for mammography at three of five eventual clinical sites. This report provides an overview of the study's design, data management system, and methodology for evaluation.

Biomechanical comparison of internal fixation techniques for the treatment of unstable basicervical femoral neck fractures.

OBJECTIVES: The optimal method of internal fixation of basicervical femoral neck fractures is controversial. This area represents a transition zone between the intracapsular femoral neck fracture, usually fixed with multiple cancellous screws, and the extracapsular interochanteric fracture, fixed with a sliding screw device [sliding hip screw (SHS)] and derotation screw (DRS) device. The authors' specific aim was to biomechanically compare these two methods of fixation in a cadaveric model of a basicervical femoral neck fracture with posteromedial comminution. DESIGN: The authors compared the average peak force during cyclic loading and the maximum axial force sustained by matched pairs of specimens stabilized with either fixation and subjected to axial and torsional loading while flexing and extending the hip. The average peak force was defined as the mean of the peak force values measured in each loading cycle with the maximum displacement of the materials tester actuator the same for each cycle (displacement control) as opposed to the maximum force being held constant (load control). RESULTS: The cancellous screw group maintained a significantly lower average peak force, 470 Newtons (SD = 145 Newtons), compared with 868 Newtons (SD = 186 Newtons) for the SHS and DRS composite group (p < 0.01). Similarly, the cancellous screw group demonstrated a lower ultimate load to failure, 1,863 Newtons (SD = 475 Newtons) compared with 3,557 Newtons (SD = 215 Newtons) for the SHS and DRS composite group (p < 0.01). CONCLUSION: The results support the use of an SHS and DHS composite compared with three cancellous screws in the treatment of unstable basicervical femoral neck fractures.

Randomized pharmacodynamic and pharmacogenetic trial of dronabinol effects on colon transit in irritable bowel syndrome-diarrhea.

BACKGROUND: Genetic variation in endocannabinoid metabolism is associated with colonic transit in irritable bowel syndrome (IBS) with diarrhea (IBS-D). The nonselective cannabinoid (CB) receptor agonist, dronabinol (DRO), reduced fasting colonic motility in nonconstipated IBS. FAAH and CNR1 variants influenced DRO's effects on colonic motility. Our aims were: (i) to compare dose-related effects of DRO to placebo (PLA) on gut transit in IBS-D, and (ii) to examine influence of genetic variations in CB mechanisms on DRO's transit effects. METHODS: Thirty-six IBS-D volunteers were randomized (double-blind, concealed allocation) to twice per day PLA (n = 13), DRO 2.5 mg (n = 10), or DRO 5 mg (n = 13) for 2 days. We assessed gastric, small bowel, and colonic transit by validated radioscintigraphy and genotyped the single nucleotide polymorphisms CNR1 rs806378 and FAAH rs324420. Data analysis utilized a dominant genetic model. KEY RESULTS: Overall treatment effects of DRO on gastric, small bowel, or colonic transit were not detected. CNR1 rs806378 CT/TT was associated with a modest delay in colonic transit at 24 h compared with CC (P = 0.13 for differential treatment effects on postminus pretreatment changes in colonic transit by genotype). No significant interaction of treatment with FAAH rs324420 was detected. CONCLUSIONS & INFERENCES: Overall, DRO 2.5 or 5 mg twice per day for 2 days had no effect on gut transit in IBS-D. There appears to be a treatment-by-genotype effect, whereby DRO preferentially delays colonic transit in those with the CNR1 rs806378 CT/TT genotypes. Further study of CB pharmacogenetics may help identify a subset of IBS-D patients most likely to benefit from CB agonist therapy.

Hypoxia and cell cycle regulation of the von Hippel-Lindau tumor suppressor.

Inactivation of von Hippel-Lindau tumor-suppressor protein (pVHL) is associated with von Hippel-Lindau disease, an inherited cancer syndrome, as well as the majority of patients with sporadic clear cell renal cell carcinoma (RCC). Although the involvement of pVHL in oxygen sensing through targeting hypoxia-inducible factor-α subunits to ubiquitin-dependent proteolysis has been well documented, less is known about pVHL regulation under both normoxic and hypoxic conditions. We found that pVHL levels decreased in hypoxia and that hypoxia-induced cell cycle arrest is associated with pVHL expression in RCC cells. pVHL levels fluctuate during the cell cycle, paralleling cyclin B1 levels, with decreased levels in mitosis and G1. pVHL contains consensus destruction (D) box sequences, and pVHL associates with Cdh1, an activator of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. We show that pVHL has a decreased half-life in G1, Cdh1 downregulation results in increased pVHL expression, whereas Cdh1 overexpression results in decreased pVHL expression. Taken together, these results suggest that pVHL is a novel substrate of APC/C(Cdh1). D box-independent pVHL degradation was also detected, indicating that other ubiquitin ligases are also activated for pVHL degradation.