Increased all-cause and cardiovascular mortality in monogenic diabetes as a result of mutations in the HNF1A gene.

AIMS: To investigate all-cause and cardiovascular mortality in subjects with diabetes caused by a mutation in the hepatocyte nuclear factor 1alpha gene (HNF1A). METHODS: We identified 39 British families with HNF1A mutations. Consenting individuals were asked details of age and cause of death of parents and siblings. Copies of death certificates were requested from the family or were obtained via the Offices for National Statistics. RESULTS: Data were collated on 241 control subjects and 153 mutation carriers. Of those who died, 66% of mutation carriers died from a cardiovascular-related illness compared with 43% of control subjects (P = 0.02). Family members with HNF1A mutations died at a younger age than familial control subjects [all-cause hazard ratio, adjusting for sex and smoking status: 1.9 (95% confidence interval 1.2, 2.9, P = 0.006; cardiovascular hazard ratio: 2.3, confidence interval 1.3, 4.2, P = 0.006)]. CONCLUSIONS: We have shown that individuals known to have diabetes caused by a mutation in the HNF1A gene have an increased risk of cardiovascular mortality compared with their unaffected family members. As with other forms of diabetes, consideration should be given to early statin therapy despite a seemingly protective lipid profile.

Effects of technique and analytic conditions on tidal breathing flow volume loops in term neonates.

The tidal breathing flow volume loop (TBFVL) may provide objective assessments of infant airway function. We examined whether infant biologic variability and technical limitations of commercial equipment might affect tidal breathing indices. TBFVLs were obtained in 79 sleeping, healthy, 1-5-day-old infants, divided into two groups: 1) TBFVLs were obtained immediately after face mask placement, i.e., within 5-20 sec (Group A), or 2) after a delay of 2-3 min following face mask placement (Group B). Both tidal volume (VT) and respiratory rates (RR) were significantly lower (25% and 20%, respectively) in Group A than in Group B. VT mean (SD) was 4.45 (0.93) ml/kg for Group A and 6.09 (1.11) ml/kg for Group B (P < 0.0001); RR was 48.4 (12.2) min-1 and 60.0 (15.60) min-1 for Groups A and B, respectively (P < 0.0003). The time to peak expiratory flow as a ratio of total expiratory time (tPTEF:tE), purported to be a useful index of airway obstruction, was also significantly (P < 0.0001) attenuated in TBFVLs obtained immediately after face mask placement; tPTEF:tE was 0.26 (0.09) and 0.37 (0.05) in Groups A and B, respectively. Reproducibility of tPTEF:tE was affected by the timing of recordings. Intraindividual coefficients of variation were greater in Group A (36.53%) than Group B (18.82%). Similarly, significant differences were observed in mean value and variability of other indices of airway function between Groups A and B. Although they are easy to perform, we conclude that tidal breathing analyses may be significantly complicated by simple differences in measurement conditions.

Outcome of criminal investigation into allegations of sexual abuse.

The aim was to study the outcome of criminal investigation into allegations of sexual abuse made by 160 children assessed over a two year period in a specialist paediatric unit in the North of England. In all, 141 of the 160 children (88%) were female, and 99 (62%) were aged under 12 years. There were 145 males and nine females named by children in allegations of sexual abuse. Fathers formed the largest single group of alleged male perpetrators (56/176). None of the nine alleged female abusers was prosecuted. Of the 145 males, 57 reached trial; 49 were convicted, an 86% conviction rate of those sent to trial and a rate of proven sexual offence (including cautions) of 44% (54/124) among men originally interviewed by the police. Twenty five per cent of children (17/68) who could have testified did so, most giving evidence against someone who was known to them. Pragmatic selection of cases for prosecution resulted in an outcome highly vindicating of the decision to prosecute. The possible effects of this process are discussed.

Transhymenal cultures for sexually transmissible organisms.

Vaginal swabs were examined for sexually transmissible organisms in 238 girls seen over a 36 month period from July 1989 to June 1992 inclusive. Three groups were seen (age range 1.5-16.1 years), 165 in group 1 in whom there had been a disclosure of sexual abuse, 35 in group 2 where there was a strong suspicion of sexual abuse, and 38 with vulvovaginitis who formed group 3. The isolation of recognised sexually transmitted organisms was low; however, of group 1 19% were colonised with Gardnerella vaginalis compared with 3% of group 2 and 3% of group 3. These figures show significant differences in the proportion of children in each group isolating only from children over the age of 8 years and in five of the six girls with Candida spp there was concern about sexual abuse. Vulvovaginitis in young children was not associated with vaginal candidiasis. The relation of findings to age is discussed and recommendations are made for testing procedures.

Effects of bicuculline on inspiratory activities in piglets.

Antagonism of the alpha receptor sub-type at gamma-aminobutyric acid (GABA) recognition sites in developing pigs was evaluated using the GABAA receptor antagonist bicuculline. The effect of bicuculline infusions was to produce an increase of phrenic and hypoglossal discharge amplitudes. This bicuculline-induced effect on discharge amplitude was manifested in autopower spectra as an increase in the power of peaks located in the medium-frequency (10-50 Hz) band. More importantly, coherence estimates were increased by bicuculline administration demonstrating GABA-mediated influences on a central pattern generator with output in the 10-50 Hz band.

Effects of GABAA receptor antagonism on inspiratory activities in kittens.

In anesthetized kittens (< 1 to 24 days old), the effects of GABAA receptor antagonism on phrenic, hypoglossal and cervical sympathetic discharges were examined by i.v. bicuculline infusions during hyperoxia and hypoxia. Administration of bicuculline during hyperoxia produced marked increases in the amplitudes of inspiratory nerve discharges. During hypoxic stimulation (10% O2), the amplitudes of inspiratory activities decreased towards or below those observed during hyperoxia; bicuculline reversed this depression and restored inspiratory discharges. Our results indicated that GABAA receptors were functional shortly after birth, acting to mediate influences shaping inspiratory activity during hyperoxic breathing and during conditions of increased chemical drive.

Phrenic and recurrent laryngeal motoneuron activities during hyperoxia and hypoxia in piglets.

We hypothesized that synchronization of inspiratory motoneurons may involve inputs from two central pattern generators (CPG): one characterized by medium-frequency (< 50 Hz) and the other by high-frequency oscillations (> or = 50 Hz). We studied phrenic and recurrent laryngeal nerve activities recorded during hyperoxia and hypoxia in Saffan anesthetized, paralyzed, and artificially ventilated piglets. Spectral analyses, derived from the full as well as partitioned halves of inspiration, showed that phrenic and recurrent laryngeal discharges contained peaks in the medium-frequency band, which were indicative of common inputs. The phrenic spectra of many animals had peaks in the high-frequency band; such peaks were uncommon in recurrent laryngeal spectra; consequently, correlated activities corresponding to high-frequency oscillations were not usually observed. Thus, it is likely that acquisition of modulating inputs from a high-frequency CPG may emerge in an age-dependent manner in different motoneuron pools. During hypoxia, both phrenic and recurrent laryngeal discharges were facilitated as shown by increases in both the amplitudes of signal-averaged histograms and the magnitudes of their respective power spectral activities. Also, there was a significant increase in the values of phrenic-recurrent laryngeal coherence estimates in the medium-frequency region. Hence, medium-frequency oscillations are more apparent in early development, perhaps to facilitate synchronization of inspiratory motoneuron activities, especially under conditions of increased chemical drive.

Central patterning of inspiratory activity in the neonatal period.

We hypothesized that synchronization of neonatal inspiratory motoneurons is achieved by common inputs from one or more central pattern generators. Such inputs are manifested in neural discharges as medium-frequency (less than 50 Hz) and/or high-frequency (greater than or equal to 50 Hz) oscillations. Furthermore, if both oscillations appeared, one or both might be gated, i.e. present only in the first or second half of inspiration. The spontaneous discharges of phrenic (C5 and C6) roots and hypoglossal nerves were recorded in anesthetized or decerebrated, vagotomized, paralyzed and artificially ventilated neonatal swine. Autopower spectral analyses showed that phrenic discharges had peaks in the medium- and/or the high-frequency band. Phrenic spectra, derived from either half of inspiration, demonstrated that, while both types of oscillation were present throughout inspiration, their amplitudes were larger during the second half of inspiration. However, comparisons of the relative distributions of power in each half of inspiration showed that the increase of high-frequency power was much larger than that of medium-frequency power during the second half of inspiration. In contrast to phrenic spectra, hypoglossal spectra had peaks only at medium-frequencies; consequently, correlated frequencies (indicative of common inputs) in phrenic-hypoglossal coherence spectra were present at those frequencies. The presence of highly correlated frequencies provided strong evidence of a medium-frequency pattern generator which may remain operative beyond the neonatal period.

Respiratory modulation of sympathetic activity in neonatal swine.

Spontaneous efferent sympathetic activity (cervical sympathetic and splanchnic nerves) was recorded simultaneously with efferent phrenic discharge, with aortic pressure, and with the electrocardiogram in less than 1- to 51-day-old neonatal swine anesthetized with Saffan (alfaxalone). Power spectral analyses of sympathetic discharge revealed a frequency range of 4-36 Hz, with peaks distributed in four regions of the spectrum (4-6 Hz, 8-15 Hz, 16-22 Hz, and 28-36 Hz). Inspiratory modulation was readily apparent since sympathetic power spectral energy was greatest during the time of phrenic activity. Alterations in pulmonary afferent inputs (e.g., lung inflation tests and/or vagotomy) altered both phrenic and sympathetic activity. Use of the respiratory-cardiac modulation ratio indicated that respiratory modulation of sympathetic activity was greater than cardiac modulation. Complex afferent inputs, i.e., fictive Valsalva maneuver, indicated an immaturity of integration within the cardiovascular regulatory system. The adult patterns of blood pressure changes and heart rate responses were delayed until approximately 1 mo of age. Calculations of Valsalva ratios (ratio of maximal R-R interval to minimal R-R interval) indicated delayed onset of heart rate responses, reflecting the maturation of cardiovascular reflexes during the neonatal period.

Computerized clinic scheduling system at the University of Michigan Medical Center.

The University of Michigan Medical Center has a flexible computerized clinic scheduling system that handles approximately 750,000 visits per year at the main hospital and satellite locations. The system includes a wide variety of fully integrated functions, including appointment booking, multiple and series scheduling, wait and reschedule lists, routine reminder notices, routine requests for medical records and radiology reports, no-show follow-up, and managerial reporting at multiple levels of detail. The system is extremely flexible, and allows separate scheduling specifications for every physician and all other resources within the system. The system is available at any of the approximately 1,800 computer terminals throughout the Medical Center, and is regularly used at approximately 400 terminals.

Effects of anesthesia on efferent phrenic activity in neonatal swine.

The effects of two levels of Saffan anesthesia (standard recording level: 2-4 mg/kg/min, and 10X recording level) and a single level of pentobarbital (5 mg/kg) on the power spectral density of efferent phrenic discharge were investigated in piglets aged from less than 1 day to 50 days. The phrenic high frequency oscillation (HFO) was present in decerebrate, unanesthetized piglets and in piglets anesthetized with Saffan, albeit reduced at 10 times recording level, but was absent under pentobarbital. The results indicate that Saffan does not have a significantly depressant effect on the phrenic HFO in developing swine.

Factors affecting central inspiratory modulation of hypoglossal motoneuron activity in newborn pigs.

In newborn pigs (4-6 days old), recordings of efferent whole hypoglossal and phrenic nerve discharges were obtained during hyperoxia (or normoxia) and during hypoxia, before and after bilateral vagotomy. With intact vagi, spontaneous hypoglossal inspiratory activity was not observed and was not elicited by either spontaneous changes of electroencephalogram (EEG) or hypoxic stimulation (15% O2 in N2). After bilateral vagotomy, some animals had episodes of spontaneous hypoglossal inspiratory activity; power spectral analysis of EEG demonstrated that this inspiratory activity appeared synchronously with shifts of major peaks in EEG spectra from the delta band (0.5-3.5 Hz) to the theta band (3.5-7.0 Hz). Hypoglossal inspiratory discharges were also elicited by hypoxic stimulation and usually had a decrementing discharge pattern; in some cases, this activity had an augmenting discharge pattern. Our results suggest that hypoglossal motoneurons are poorly modulated by central inspiratory drive, requiring additional facilitatory influences, i.e. corticobulbar, intra-bulbar, chemical drive, before such modulation is observed.

Power spectral analyses of inspiratory activities in neonatal pigs.

In anesthetized neonatal pigs, spectral analyses were done for inspiratory nerve and neuronal activities. Peaks in power spectra of phrenic roots were observed at high frequencies and at medium frequencies. In contrast, peaks in recurrent laryngeal and hypoglossal nerve spectra were found only at medium frequencies. Significant coherence estimates were obtained only at medium frequencies, indicating that different motoneuron pools share inputs from a common neural oscillator.

Age-related changes in power spectra of efferent phrenic activity in the piglet.

Power spectral analysis of phrenic nerve discharge in neonatal swine revealed the presence of both high-frequency oscillations (HFO) (95-150 Hz) and medium-frequency oscillations (MFO) (15-35 Hz). The HFO was shown to be age-related; the MFO was not. The data indicated that at least one manifestation of maturation of the respiratory rhythm generator is the increase with age of the frequency of the HFO.

Discharge properties of dorsal medullary inspiratory neurons in newborn pigs.

The discharges of medullary inspiratory neurons were recorded in newborn pigs. They were classified by discharge pattern; response to lung inflation; synaptic relation to phrenic motoneurons. Our results showed: these neurons have similar discharge patterns and responses to lung inflation as adult cats; most neurons do not project to phrenic motoneurons. It is suggested that our sampled population of neurons is involved in integrating pulmonary afferent inputs.