[Collected data on freehand technique instrumentation and literature comparison on fluoroscopic and CT-assisted navigation]. / Erhobene Daten zur Instrumentierung in Freihandtechnik und Literaturvergleich zu fluoroskopisch- und CT-gestützter Navigation.

BACKGROUND: A proven and frequently used surgical procedure in patients with idiopathic scoliosis (IS) is posterior transpedicular corrective spondylodesis using the freehand technique. Novel procedures with fluoroscopically and computed tomography (CT)-assisted navigation are presumed to be less risky and more accurate. OBJECTIVE: Is the freehand technique for IS safe with respect to screw-associated complications and intraoperative radiation exposure? MATERIAL AND METHODS: Prospectively collected data (2017-2018) from 39 consecutive patients (average age 18.7 years) with thoracic single curvature IS (61.7°â€¯± 13.9°) from a specialized scoliosis center were evaluated for the following parameters (mean ± standard deviation): total radiation product, fluoroscopy time, fused segments, operative time, blood loss and screw-associated complications. A comparison with data from the literature on intraoperative radiation exposure using navigation procedures was carried out. RESULTS: The total radiation product per patient was 71.7 ± 44.0 cGy*cm2, fluoroscopy time 17.4 ± 8.6 s. (7.8 segments), operative time 183.5 ± 54.2 min and blood loss 379.5 ± 183 ml. There were no screw-associated complications in the entire collective. Correction of the main curvature was 75.7%. Comparison of the data with index data from the literature showed a 1.25-12.5-fold higher radiation exposure for patients with fluoroscopically assisted navigation and 9.25-12.3-fold higher radiation exposure with CT-assisted procedures compared to the present results. CONCLUSION: The results of this study showed that with appropriate experience freehand positioning of pedicle screws is associated with comparable accuracy and less radiation exposure for patients than navigation procedures. With respect to the young age of patients, a radiation-induced long-term risk for malignant diseases should be taken into consideration.

N-methyl-D-aspartate antagonists limit aminoglycoside antibiotic-induced hearing loss.

The use of aminoglycoside antibiotics is limited by ototoxicity that can produce permanent hearing loss. We report that concurrent administration of N-methyl-D-aspartate (NMDA) antagonists markedly attenuates both the hearing loss and destruction of cochlear hair cells in guinea pigs treated with aminoglycoside antibiotics. These findings indicate that aminoglycoside-induced hearing loss is mediated, in part, through an excitotoxic process. The high correlation (Spearman correlation coefficient: 0.928; P < 0.01) obtained between the relative cochleotoxicities of a series of aminoglycosides in humans and the potencies of these compounds to produce a polyamine-like enhancement of [3H]dizocilpine binding to NMDA receptors is consistent with this hypothesis, and provides a simple in vitro assay that can predict this aspect of aminoglycoside-induced ototoxicity.

OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele.

INTRODUCTION: The majority of hearing loss in children can be accounted for by genetic causes. Non-syndromic hearing loss accounts for 80% of genetic hearing loss in children, with mutations in DFNB1/GJB2 being by far the most common cause. Among the second tier genetic causes of hearing loss in children are mutations in the DFNB9/OTOF gene. METHODS: In total, 65 recessive non-syndromic hearing loss families were screened by genotyping for association with the DFNB9/OTOF gene. Families with genotypes consistent with linkage or uninformative for linkage to this gene region were further screened for mutations in the 48 known coding exons of otoferlin. RESULTS: Eight OTOF pathological variants were discovered in six families. Of these, Q829X was found in two families. We also noted 23 other coding variant, believed to have no pathology. A previously published missense allele I515T was found in the heterozygous state in an individual who was observed to be temperature sensitive for the auditory neuropathy phenotype. CONCLUSIONS: Mutations in OTOF cause both profound hearing loss and a type of hearing loss where otoacoustic emissions are spared called auditory neuropathy.

The mouse deafness locus (dn) is associated with an inversion on chromosome 19.

Recombination data for the mouse deafness locus (dn) on chromosome 19 are consistent with the presence of an inversion for which one of the breakpoints is between D19Mit14 and D19Mit96, a distance of less than 226 kb. Fluorescence in situ hybridization studies using a bacterial artificial chromosome on interphase (G1) nuclei provide additional support for the presence of an inversion. The dn gene is probably the orthologue of the human DFNB7/DFNB11 gene on chromosome 9.

The architectural transition of human complement component C9 to poly(C9).

Several regions of C9 including three cysteine-rich modules homologous to those in thrombospondin (TS), the low density lipoprotein receptor (LDL), the epidermal growth factors (EDGF), as well as two middle sections of the polypeptide chain were expressed in bacteria. Antibodies derived from these segments were used to probe the relative exposure of epitopes in C9 and poly(C9) using ELISAs. The results indicated that the TS and LDL modules are fully exposed in both monomer and polymer; however, the middle region of the polypeptide chain is buried in the monomer but external in the polymer. Using specified conditions, Fab fragments to the TS and LDL modules did not block C9 polymerization, but those to the middle region of the polypeptide chain and to some extent to the EDGF module did so. Immuno-electron microscopy of poly(C9) indicated that the C9 polypeptide chain assumes a 'U' shape, in which the TS and LDL modules are located on the upper rim. The EDGF module is located on the lower edge of the upper rim, and midsection of the polypeptide chain constructs the barrel of the tubule. Computer assisted contrast enhancement of select electron micrograph images of poly(C9) allowed the clear visualization of each subunit. These were seen to have a volute shape. The upper rim is composed of whorls that are apparently not in lateral contact. It is concluded that the TS and LDL modules do not participate directly in polymerization but cover the hydrophobic central region of the polypeptide chain in the monomer. As a consequence of circular polymerization the midsection of the polypeptide chain becomes exposed as each C9 lengths to fashion a volute form. reserved.

The efficacy and safety of miglitol therapy compared with glibenclamide in patients with NIDDM inadequately controlled by diet alone.

OBJECTIVE: To compare the therapeutic effects of the alpha-glucosidase inhibitor miglitol (BAY m 1099), the sulfonylurea glibenclamide, and placebo on parameters of metabolic control and safety in patients with NIDDM that is inadequately controlled by diet alone. RESEARCH DESIGN AND METHODS: After a 4-week placebo run-in period, 201 patients in 18 centers in 4 countries were randomized in a double-blind manner to miglitol (50 mg t.i.d., followed by 100 mg t.i.d.), glibenclamide (3.5 mg q.d/b.i.d.), or placebo for 24 weeks. Efficacy criteria were changes from baseline of HbA1c, fasting and postprandial blood glucose and insulin levels, body weight, and serum triglycerides. RESULTS: Efficacy was assessed in 119 patients who completed the full protocol, and the results were similar to those obtained in 186 patients who fulfilled the validity criteria for analysis. Compared with placebo, mean baseline-adjusted HbA1c decreased by 0.75% (P = 0.0021) and 1.01% (P = 0.0001) in the miglitol and glibenclamide treatment groups, respectively. Blood glucose decreased slightly in the fasting state and considerably in the postprandial state in both treatment groups but not in the placebo group. Fasting insulin levels increased slightly (NS) in all treatment groups; however, postprandial insulin levels decreased with miglitol, while increasing markedly with glibenclamide (P = 0.0001 between all treatment groups). Gastrointestinal side effects (flatulence and diarrhea) occurred mostly in the miglitol-treated patients, while some glibenclamide-treated patients had symptoms suggestive of hypoglycemia. CONCLUSIONS: Miglitol monotherapy is effective and safe in NIDDM patients. Compared with glibenclamide, it reduced HbA1c less effectively and caused more gastrointestinal side effects. On the other hand, glibenclamide, unlike miglitol, tended to cause hypoglycemia, hyperinsulinemia, and weight gain, which are not desirable in patients with NIDDM.

Mapping the HLA ligandome landscape of acute myeloid leukemia: a targeted approach toward peptide-based immunotherapy.

Identification of physiologically relevant peptide vaccine targets calls for the direct analysis of the entirety of naturally presented human leukocyte antigen (HLA) ligands, termed the HLA ligandome. In this study, we implemented this direct approach using immunoprecipitation and mass spectrometry to define acute myeloid leukemia (AML)-associated peptide vaccine targets. Mapping the HLA class I ligandomes of 15 AML patients and 35 healthy controls, more than 25 000 different naturally presented HLA ligands were identified. Target prioritization based on AML exclusivity and high presentation frequency in the AML cohort identified a panel of 132 LiTAAs (ligandome-derived tumor-associated antigens), and 341 corresponding HLA ligands (LiTAPs (ligandome-derived tumor-associated peptides)) represented subset independently in >20% of AML patients. Functional characterization of LiTAPs by interferon-γ ELISPOT (Enzyme-Linked ImmunoSpot) and intracellular cytokine staining confirmed AML-specific CD8(+) T-cell recognition. Of note, our platform identified HLA ligands representing several established AML-associated antigens (e.g. NPM1, MAGED1, PRTN3, MPO, WT1), but found 80% of them to be also represented in healthy control samples. Mapping of HLA class II ligandomes provided additional CD4(+) T-cell epitopes and potentially synergistic embedded HLA ligands, allowing for complementation of a multipeptide vaccine for the immunotherapy of AML.

Antipyrine disposition in milk and saliva of lactating women.

Widely used to study hepatic drug metabolism, antipyrine rapidly distributes in total body water. Antipyrine distribution was studied in seven lactating women. Duration of lactation ranged from 2 to 19 mo. In all subjects the drug was rapidly absorbed; in five women peak concentrations were attained in milk and saliva by 1 hr and in the other two women by 3 hr (first point at which collections were made). In two women in whom antipyrine was measured at 10-min intervals during the first hour, peak concentrations in both milk and saliva were attained by 10 min after antipyrine. The time course for antipyrine disappearance from milk paralleled that from saliva for each subject. Antipyrine half-life (t1/2) varied from 5.6 to 20.3 hr for saliva (mean +/- SD = 11.5 +/- 4.8) and from 5.7 to 21.7 hr for milk (mean +/- SD = 11.6 +/- 5.4). In the two women with the shortest salivary antipyrine t1/2 (5.6 and 7.5 hr), antipyrine was readministered many months later, after they had stopped lactating. The salivary antipyrine t1/2 rose from 5.6 to 13.3 hr in one subject and from 7.5 to 14.6 hr in the other. The corresponding decrease in antipyrine clearance was 0.93 to 0.55 and 1.41 to 0.60 ml/min/kg. This observation suggests that in some subjects lactation may influence drug metabolism. The amount of antipyrine available to each nursing infant was estimated by assuming the the infant nursed 3 ounces every 4 hr for 24 hr after maternal antipyrine administration. The amount of antipyrine available to the nursing infant was calculated to range from 3.0 to 11.1 mg (mean +/- SD = 6.4 +/- 2.9 mg) or from 0.25% to 1.07% (mean +/- SD = 0.59 +/- 0.29%) of the maternal dose.

Quinine-induced alterations in drug disposition.

In normal volunteers, chronic quinine administration shortened plasma antipyrine half-life and significantly increased the intraindividual correlation between the disposition of quinine and antipyrine. Decreased plasma antipyrine half-life appears to be due to a quinine-induced enhancement of antipyrine metabolism. A dose-dependent prolongation of plasma quinine half-life was observed and attributed primarily to an increased apparent volume of distribution of quinine, although our data did not permit separation of an effect on quinine metabolism from an effect on quinine distribution between the peripheral and central compartments. Plasma protein binding of quinine was similar at both the low and high doses of quinine. Studies in dogs given quinine intravenously revealed a biphasic plasma decay curve compatible with a 2-compartment open model for quinine disposition. Dose dependence of plasma quinine half-life in the dog after intravenous quinine eliminated altered gastrointestinal absorption of quinine as a cause for the dose dependence of plasma quinine half-life. These studies illustrate the importance of such conditions as dose and time of administration in determining the type and magnitude of interaction observed between drugs.

Disposition of dietary caffeine in milk, saliva, and plasma of lactating women.

Caffeine is present in many dietary substances; its appearance from these sources in human milk has not previously been studied in detail. Fifteen lactating women ingested a known amount of a caffeinated beverage (36 to 335 mg). Simultaneous milk and saliva samples were collected at intervals for the subsequent 12 hours and assayed for caffeine content. Eleven of 15 mothers excreted measurable caffeine in milk. Caffeine was detected by 15 minutes in saliva and milk; peak levels in milk (2.09 to 7.17 micrograms/mL) and saliva (1.24 to 9.22 micrograms/mL) were achieved within 1 hour. Elimination half-lives were 1.3 to 13.5 hours (mean 4.0 +/- 3.7 [SD] hours) for saliva and 1.5 to 14.5 hours (mean 6.1 +/- 4.4 [SD] hours) for milk. Assuming each infant would ingest 90 mL of milk every three hours for 24 hours after maternal ingestion of caffeine, it is possible to estimate potential exposure of the nursing infant to caffeine. The amount of caffeine available for infant absorption ranged from 0.01 to 1.64 mg or 0.06% to 1.5% of the maternal dose. Caffeine was not present in the infants' urine collected for five hours after the first nursing period. The maternal ingestion of a single cup of caffeinated beverage does not appear to present significant doses of caffeine to the nursing infant.

Infant exposure to chemicals in breast milk in the United States: what we need to learn from a breast milk monitoring program.

The presence of environmental chemicals in breast milk has gained increased attention from regulatory agencies and groups advocating women's and children's health. As the published literature on chemicals in breast milk has grown, there remains a paucity of data on parameters related to infant exposure via breast-feeding, particularly those with a time-dependent nature. This information is necessary for performing exposure assessments without heavy reliance on default assumptions. Although most experts agree that, except in unusual situations, breast-feeding is the preferred nutrition, a better understanding of an infant's level of exposure to environmental chemicals is essential, particularly in the United States where information is sparse. In this paper, we review extant data on two parameters needed to conduct realistic exposure assessments for breast-fed infants: a) levels of chemicals in human milk in the United States (and trends for dioxins/furans); and b) elimination kinetics (depuration) of chemicals from the mother during breast-feeding. The limitations of the existing data restrict our ability to predict infant body burdens of these chemicals from breast-feeding. Although the data indicate a decrease in breast milk dioxin toxic equivalents over time for several countries, the results for the United States are ambiguous. Whereas available information supports the inclusion of depuration when estimating exposures from breast-feeding, the data do not support selection of a specific rate of depuration. A program of breast milk monitoring would serve to provide the information needed to assess infant exposures during breast-feeding and develop scientifically sound information on benefits and risks of breast-feeding in the United States.

Clinical diagnosis of the Usher syndromes. Usher Syndrome Consortium.

The Usher syndromes are genetically distinct disorders which share specific phenotypic characteristics. This paper describes a set of clinical criteria recommended for the diagnosis of Usher syndrome type I and Usher syndrome type II. These criteria have been adopted by the Usher Syndrome Consortium and are used in studies reported by members of this Consortium.

Pharmacologic considerations of drug use in the lactating mother.

The recent increase in the incidence of breast-feeding has given impetus to the study of the excretion of drugs and chemicals into human milk. It appears that the major route of drug appearance in milk is via diffusion from the maternal circulation. In general, maternal plasma levels of a drug dictate milk levels. Un-ionized drugs with high lipid solubility and minimal binding to maternal plasma protein diffuse best. The amount of a drug excreted in milk is usually not more than 1 to 2% of the maternal dose. Most studies have been done with single-dose or short-term drug administration. Very few data are available for the mother who receives continuous drug therapy. Environmental chemicals such as insecticides are also a cause for special concern. They are highly lipid soluble and may remain in body fat for very long periods. Indeed, lactation may be the only route of elimination. The effect of even small amounts of these agents on the growing infant is unknown. Further studies are needed to determine the amount of these agents secreted and the possible risk to the nursing infant.

Guinea pigs show post-natal stability in frequency mapping at the basal turn.

Others have shown that in animals born with immature cochleae the basal turn undergoes changes in function during the early days of postnatal life. We examined whether similar changes could be detected in the guinea pig, an animal born with a functionally mature cochlea. Our results indicate that no changes occur in the function of the basal turn of the guinea pig cochlea immediately after birth.

Auditory evoked potentials differ at 50 milliseconds in right- and left-handed listeners.

Left-handed individuals show a 4 ms later Wave Pb in the 45-60 ms latency range of the auditory middle latency response (MLR) than right-handed individuals. Examination of auditory evoked potentials in fifteen right-handed and fifteen left-handed normal hearing adults showed that this difference was not evident in time periods earlier or later than 45-60 ms. The isolation of this latency difference to a specific time period suggests that the source or sources of Wave Pb may be an independent physiological index which correlates with hand preference.

Does type I afferent neuron dysfunction reveal itself through lack of efferent suppression?

We present here two patients and three control subjects to demonstrate the clinical utility of studying evoked otoacoustic emissions and their contralateral suppression, as an aid to the delineation of afferent neuron dysfunction and possible lack of efferent suppression. The key patients here who fail to show contralateral suppression of their very robust otoacoustic emissions, concomitantly show paradoxically absent auditory brainstem responses (ABRs) and absence of middle ear muscle reflexes despite normal audiograms in the 2 kHz region and normal tympanograms. One of these patients has nearly normal pure tone sensitivity up to 3 kHz. The other has normal sensitivity in the 2 kHz region, but poor sensitivity on either side of that frequency. In addition, the two patients of interest show absent masking level differences and inordinately poor speech discrimination. Three 'foils' are presented: one patient with poor hearing on either side of 2 kHz, one with Bell's Palsy, and the third with bilateral temporal lobe disease. These patients show respectively that (1) isolated normal hearing at 2 kHz, (2) absence of middle ear muscle reflexes and (3) conscious cortical awareness of sound do not contribute directly to this intriguing clinical state. We propose that these patients with absent ABRs suffer from an auditory nervous system dysfunction which disrupts access to the efferent system. This condition also disables whatever systems contribute to the neural synchrony inherent in recording compound far-field action potentials such as the ABR. There are a number of hypotheses to be considered here. One suggests that the key patients are deficient in synchronous activation of Type I afferent fibers to the degree that they cannot activate efferent feedback, or they may be able to use only so-called Type II afferent neurons to support their normal zones of pure tone sensitivity. A less likely consideration focuses on the notion that discharge of primary neurons might be in some way synchronized by an efferent system which in these patients is the primary source of deficit.

Development of contralateral suppression of the VIIIth nerve compound action potential (CAP) in the Mongolian gerbil.

We studied whether same-frequency contralateral tones of 65 dB pSPL (peak Sound Pressure Level) suppress the VIIIth nerve compound action potential (CAP) evoked by 40-45 dB pSPL tone pips in the Mongolian gerbil from 22 to 92 days after birth (DAB). The primary stimuli were tone pips of 1, 2, 4, 8, and 10 kHz; only the 1 kHz CAP amplitude was suppressed significantly by tones of the same frequency. The suppression was seen at 22 DAB, and underwent little relative change with development.

Derived guinea pig compound VIIIth nerve action potentials to continuous pure tones.

A technique is described which verifies neural activity to a very faint continuous sine wave through subtraction of two different far-field whole nerve action potentials from one another. A brief transient is presented to an animal in order to elicit a supra-threshold action potential. The technique is then repeated, but on the second trial a near-threshold sine wave is mixed with the transient and another action potential is collected. The resultant evoked is then subtracted from the evoked potential generated by the transient alone and a small but persistent difference potential is acquired that presumably represents the unit activity occupied by the continuous sine wave. Four experiments are presented to show the validity of this technique, along with a surprising stability of the derived-response latency despite a 30 dB range of the probes. The technique may have promise in predicting behavioral responses to sinusoids acquired from individual animals.

Development of the VIIIth nerve compound action potential evoked by low-intensity tone pips in the Mongolian gerbil.

Maturation of the cochlea and afferent auditory units is reflected by changes in VIIIth nerve compound action potential (CAP) parameters. We studied auditory nerve CAPs evoked by low-intensity stimuli in Mongolian gerbils (Meriones unguiculatus) ranging in age from 22 to 92 days after birth. The gerbil CAP development is characterized by marked changes in latency, threshold, and amplitude during the first few weeks of life. CAP latency and CAP threshold reach adult-like values at about 1 month of age. In contrast, the CAP amplitude continues to grow in size even after 2 months. This dichotomy suggests that the development of afferent auditory nerve function in the gerbil is preceded by maturation of the mechanical processes of the middle ear and cochlea.