Diabetes UK Position Statement. Competency frameworks in diabetes.

The quality, skills and attitudes of staff working in the healthcare system are central to multidisciplinary learning and working, and to the delivery of the quality of care patients expect. Patients want to know that the staff supporting them have the right knowledge and attitudes to work in partnership, particularly for conditions such as diabetes where 95% of all care is delivered by the person with diabetes themselves. With the current changes in the NHS structures in England, and the potential for greater variation in the types of 'qualified provider', along with the recent scandal at Mid-Staffordshire Hospital, staff need to be shown to be competent and named/accredited or recognized as such. This will help to restore faith in an increasingly devolved delivery structure. The education and validation of competency needs to be consistently delivered and assured to ensure standards are maintained for different roles and disciplines across each UK nation. Diabetes UK recommends that all NHS organizations prioritize healthcare professional education, training and competency through the implementation of a National Diabetes Competency Framework and the phased approach to delivery to address this need.

Prediction of somatic and non-somatic depressive symptoms between inpatient rehabilitation and follow-up.

STUDY DESIGN: Longitudinal. OBJECTIVE: We identified changes in the association of somatic and non-somatic symptoms (as measured by the Patient Health Questionnaire-9, PHQ-9) between inpatient rehabilitation after spinal cord injury (SCI) and 1 year after discharge. SETTING: A specialty hospital in the Southeastern USA. METHODS: A total of 584 adults with traumatic SCI were administered the PHQ-9 during inpatient rehabilitation. Of them, 227 completed the PHQ-9 by survey at 1-year follow-up. We performed time-lagged regression between times of measurement for somatic and non-somatic factors of the PHQ-9. RESULTS: The non-somatic factor at baseline was significantly predictive of the non-somatic (r=0.67, P=0.002) and somatic factors at follow-up (r=0.53, P=0.019). The somatic factor did not significantly predict either the somatic (r=0.10, n.s.) or non-somatic factors at follow-up (r=-0.01, NS). Factor analysis also indicated changing factor structure between inpatient rehabilitation and follow-up. CONCLUSIONS: Our results question the interpretation of somatic items during inpatient rehabilitation, as they are not predictive of either somatic or non-somatic symptoms at follow-up.

IL-13 stimulates vascular endothelial cell growth factor and protects against hyperoxic acute lung injury.

Hyperoxia is an important cause of acute lung injury. To determine whether IL-13 is protective in hyperoxia, we compared the survival in 100% O(2) of transgenic mice that overexpress IL-13 in the lung and of nontransgenic littermate controls. IL-13 enhanced survival in 100% O(2). One hundred percent of nontransgenic mice died in 4-5 days, whereas 100% of IL-13-overexpressing mice lived for more than 7 days, and many lived 10-14 days. IL-13 also stimulated VEGF accumulation in mice breathing room air, and it interacted with 100% (2) to increase VEGF accumulation further. The 164-amino acid isoform was the major VEGF moiety in bronchoalveolar lavage from transgenic mice in room air, whereas the 120- and 188-amino acid isoforms accumulated in these mice during hyperoxia. In addition, antibody neutralization of VEGF decreased the survival of IL-13-overexpressing mice in 100% (2). These studies demonstrate that IL-13 has protective effects in hyperoxic acute lung injury. They also demonstrate that IL-13, alone and in combination with 100% (2), stimulates pulmonary VEGF accumulation, that this stimulation is isoform-specific, and that the protective effects of IL-13 are mediated, in part, by VEGF.

Synaptic abnormalities of mice lacking toll-like receptor (TLR)-9.

Motor, sensory, and autonomic abnormalities are reported for toll-like receptor 9 (TLR9) knock-out (KO) mice. However, a physiological role of TLR9 in the nervous system is largely unknown. Since altered synaptic transmission can contribute to sensory and motor abnormalities, we evaluated neuromuscular junction (NMJ) function and morphology of TLR9 KO mice. Triangularis sterni nerve-muscle preparations were dissected from TLR9 KO and age-matched control mice. Two-electrode voltage clamp of the motor endplate revealed that the amplitude and frequency of miniature end plate currents (mEPCs) for TLR9 KO NMJs were significantly greater than control. In contrast, mean endplate current (EPC, 1Hz) amplitude was equivalent to control. The ratio of mean EPC to mean mEPC amplitude indicated a decline of quantal content (m) for TLR9 KO NMJs. Furthermore, m declined more rapidly than control in response to 50-Hz stimulus trains. A rightward shift of the mEPC amplitude distribution suggested formation of vesicles containing larger amounts of acetylcholine (ACh). Staining with rhodamine α-bungarotoxin revealed a significant decline of endplate size in TLR9 KO mice. This alteration may result from ACh-induced decline of acetylcholine receptor (AChR) expression resulting from increased frequency and amplitude of mEPCs. At the same time, excessive spontaneous vesicular ACh release may initiate retrograde suppression of excitation-secretion coupling. These data suggest a novel role of TLR9 in the development of the NMJ.

Convergence of pre- and postsynaptic influences on glucosensing neurons in the ventromedial hypothalamic nucleus.

Glucosensing neurons in the ventromedial hypothalamic nucleus (VMN) were studied using visually guided slice-patch recording techniques in brain slices from 14- to 21-day-old male Sprague-Dawley rats. Whole-cell current-clamp recordings were made as extracellular glucose levels were increased (from 2.5 to 5 or 10 mmol/l) or decreased (from 2.5 to 0.1 mmol/l). Using these physiological conditions to define glucosensing neurons, two subtypes of VMN glucosensing neurons were directly responsive to alterations in extracellular glucose levels. Another three subtypes were not directly glucose-sensing themselves, but rather were presynaptically modulated by changes in extracellular glucose. Of the VMN neurons, 14% were directly inhibited by decreases in extracellular glucose (glucose-excited [GE]), and 3% were directly excited by decreases in extracellular glucose (glucose-inhibited [GI]). An additional 14% were presynaptically excited by decreased glucose (PED neurons). The other two subtypes of glucosensing neurons were either presynaptically inhibited (PIR; 11%) or excited (PER; 8%) when extracellular glucose was raised to > 2.5 mmol/l. GE neurons sensed decreased glucose via an ATP-sensitive K(+) (K(ATP)) channel. The inhibitory effect of increased glucose on PIR neurons appears to be mediated by a presynaptic gamma-aminobutyric acid-ergic glucosensing neuron that probably originates outside the VMN. Finally, all types of glucosensing neurons were both fewer in number and showed abnormal responses to glucose in a rodent model of diet-induced obesity and type 2 diabetes.

A study of the reinnervation of fast and slow mammalian muscles.

Miniature end plate potential (mepp) frequency in innervated extensor muscle is significantly higher than in soleus muscle. 9 days after nerve crush mepps of low amplitude and prolonged duration reappeared at a frequency of 2% of control and were similar to normal muscles after 35 days. Membrane potential began to increase 9-10 days after nerve crush and at 30 days was similar to controls. The region most sensitive to ACh in denervated and reinnervated muscles was the end plate. Caffeine (20 mM, 23 degrees C) induced contracture in innervated soleus but not in extensor muscles. After denervation the extensor became sensitive to caffeine while the soleus muscles decreased in sensitivity to the drug; 4-5 days after reinnervation the effect of caffeine on these muscles was similar to control. The events during reinnervation are: (a) reappearance of mepps at the same time as end plate potential and muscle twitch; (b) partial restoration of the membrane potential; (c) return of caffeine-induced contracture to normal levels in the soleus and its absence in the extensor muscles; (d) return of membrane resistance to normal values in both muscles at about 25 days; and (e) return of ACh-sensitivity to control levels at about 30 days in both muscles. Although these results suggest that the membrane potential and sarcoplasmic reticulum are under neural influence, it remains to be established whether or not separate neurotrophic factors are involved.

Action potentials in fast- and slow-twitch mammalian muscles during reinnervation and development.

Action potentials (APs) were recorded from the extrajunctional membrane of surface fibers of the fast-twitch extensor digitorum longus (extensor) and the slow-twitch soleus muscles of adult rats. APs of the extensor muscle had a significantly faster rate of rise and fall, as well as a shorter duration, than those of the soleus. In addition, the overshoot of APs and the resting membrane potential was greater for the extensor. Whereas the soleus produced only one AP regardless of the stimulus duration, the number of extensor responses was directly proportional to the stimulus duration. This repetitive activity was greatly reduced by a concentration of tetrodotoxin (TTX) as low as 5 X 10(11) g/ml. Within 8 d after crush of the nerves to these two muscles, all differences in AP properties disappeared and both muscles became partially resistant to TTX. Reinnervation brought about a redifferentiation so that differences in AP were again significant at 22 d after nerve crush. However, the rate of rise of extensor APs did not attain normal values even as late as 60 d after nerve crush. APs were found to be the same for extensor and soleus muscles from 12-d-old rats. At 18 d after birth, rate of rise was equivalent to that of adult muscle for the soleus although 50--60 d were required before this parameter was fully mature for the extensor. Nevertheless, APs of the extensor and soleus were clearly differentiated within 25 d after birth. Differences in fast and slow muscle APs are discussed with regard to differences in ion gradients and sarcolemmal conductance.

Clinicopathologic studies of thymic carcinoids in multiple endocrine neoplasia type 1.

Thymic carcinoid is part of the multiple endocrine neoplasia type 1 (MEN1) syndrome occurring predominantly in male patients who were heavy smokers, presenting most commonly in middle age. In contrast with metastatic midgut carcinoids, MEN1-related thymic carcinoid is not associated with carcinoid syndrome, nor is it associated with Cushing syndrome, in contrast with sporadic thymic carcinoids. Local invasion and metastasis are common. Prognosis is poor because of late detection, lack of effective treatment, and the aggressive nature of the tumor. All patients with thymic carcinoids should be investigated for MEN1, including thorough clinical evaluation and family studies. Anterior mediastinal lesions in MEN1 male patients should be considered thymic carcinoids until proven otherwise. All male MEN1 patients and asymptomatic gene carriers should be warned of the risk of thymic carcinoids and the possible link to smoking. Computed tomography (CT) of the chest is recommended on first screening for MEN1 in male patients more than 25 years of age, followed by yearly chest X-rays and chest CT every 3 years. Prophylactic thymectomy should be carried out during subtotal or total parathyroidectomy on MEN1 patients.

Primary rhabdomyosarcoma of the adult liver.

A 53-year-old male Caucasian presented with a massive liver tumor composed entirely of spindle-shaped cells showing light-microscopic and ultrastructural evidence of rhabdomyoblastic differentiation. No epithelial or other sarcomatous elements were included. Detailed postmortem examination failed to reveal evidence of metastatic tumor or an alternative primary site. There have been only four previous cases of primary rhabdomyosarcoma of the adult liver, all occurring in Japanese men.

Excitatory amino acid induced currents of isolated murine hypothalamic neurons and their suppression by 2,3-butanedione monoxime.

Ionic currents induced by excitatory amino acids were investigated for freshly isolated murine hypothalamic neurons with whole cell recording techniques. L-glutamate or N-methyl-D-aspartate (NMDA), in combination with glycine, resulted in a rapidly rising current which decayed in the continued presence of agonist. In contrast, kainate currents did not decay. While quisqualate-induced current maintained a steady amplitude in the continued presence of agonist, a rapid decay phase appeared at holding potentials negative to -50 mV. Co-application of 2,3-butanedione monoxime (BDM) reversibly inhibited the currents due to each agonist. Detailed study of BDM suppression of kainate-induced current revealed two components. A component with a rapid onset did not involve phosphatase action since 500 microM ATP-gamma-S or a protein kinase inhibitor (H-7, 200 microM) did not alter current suppression or recovery after BDM. Thus, the probable mechanism for this component of BDM's effect is direct block of the kainate-activated ion channel. However, preincubating neurons with 30 mM BDM reduced their subsequent response to kainate alone. This persistent effect of BDM was not seen for neurons dialyzed with a solution containing ATP-gamma-S during conventional whole cell recording. Furthermore, exposure to H-7 prevented recovery of the kainate response suppressed by preincubation in BDM. These findings suggest that BDM causes sustained suppression of the kainate response of hypothalamic neurons via a "chemical phosphatase" action.

Decay of ethanol-induced suppression of glycine-activated current of ventral tegmental area neurons.

We demonstrated previously that ethanol depresses glycine-induced currents in 45% of neurons freshly isolated from the ventral tegmental area (VTA) of rats (), and that protein kinase C (PKC) modulates this action of ethanol (). In the present study, we investigated the time course of this effect of ethanol on VTA neurons from young rats. For 70% of the neurons in which ethanol reduced glycine-evoked currents, this depressant effect gradually diminished during continuous superfusion with ethanol. Its action decayed faster when ethanol was applied in several brief pulses than by continuous superfusion. On the other hand, the decay was especially slower when ethanol was applied in pulses at longer intervals or by preincubation. Phorbol ester 12,13-dibutyrate (PDBu, 1 microM), an activator of PKC, also depressed glycine-induced currents. In approximately 40% (6/15) of the neurons, the effect of PDBu diminished with time and was antagonized by the specific PKC inhibitor, chelerythrine (7 microM). Chelerythrine also attenuated the ethanol-induced depression of glycine-induced currents and its time-dependent decay, thus confirming our previous evidence that PKC mediates, at least in part, the decay of the depressant effect of ethanol on glycine-induced currents of VTA neurons.

Elevated density and altered pharmacologic properties of myocardial calcium current of the spontaneously hypertensive rat.

DESIGN: The membrane current mediated by the L-type calcium channel (ICa) was studied for myocytes isolated from the ventricle of 10- to 11-week-old spontaneously hypertensive rats (SHR). RESULTS: Compared with age-matched normotensive Wistar-Kyoto (WKY) or Sprague-Dawley rats, the amplitude of ICa was greater for the SHR. Two observations suggest that the greater ICa of the SHR was not due to hypertrophy. First, the similarity of membrane capacitance for these three strains of rat indicated lack of hypertrophy. Secondly, the amplitude of ICa was also greater for myocytes isolated from the right ventricle of the SHR. The ICa of the SHR was more sensitive to drugs known to activate calcium channels via phosphorylation. Specifically, extracellular application of 1 mumol/l isoprenaline as well as intracellular dialysis with either 1 mmol/l cyclic AMP or with 1 mmol/l adenosine 5'-O-3-thiotriphosphate increased the mean ICa of SHR myocytes significantly more than that of WKY rat cells. The ICa of SHR myocytes was also more sensitive to BAY K 8644 and its enantiomorphs. CONCLUSION: The present data suggest that the greater peak amplitude of ICa for SHR myocytes relative to that of myocytes of normotensive rats is due to an increase in current density and enhancement of channel phosphorylation.

Effects of butanedione monoxime on neuromuscular transmission.

1. The amplitude of endplate potentials was increased by concentrations of butanedione monoxime (BDM, 5-20 mM) that typically caused muscle paralysis. 2. Although BDM slowed the decay of spontaneous miniature endplate currents, the effect was insufficient to explain most of the large increase in amplitude of endplate potentials. 3. The quantal content of endplate potentials was increased by BDM in a reversible, concentration-dependent manner. 4. The frequency of miniature endplate potentials was not changed by 10 mM BDM in the presence of normal or raised potassium concentrations, indicating that BDM does not change quantal content by a direct effect on calcium channels or on steady-state intracellular calcium concentration. 5. A change in the time course of the extracellularly recorded nerve terminal action potential caused by BDM was similar to the change produced by 4-aminopyridine (4-AP). 6. The increase in quantal content produced by BDM was only slightly reduced in the presence of 1 mM tetraethylammonium (TEA) but was significantly reduced in the presence of 0.5 to 1 mM 4-AP. 7. It was concluded that BDM blocks a 4-AP-sensitive potassium conductance in motor nerve terminals and, by increasing the duration of the action potential in this way, increases evoked transmitter release.

Distribution of dysplasias and early invasive carcinoma in Barrett's esophagus.

To assess the anatomic relationships between areas of dysplasia and "early" carcinoma, we evaluated histologically the entire mucosal surfaces of seven esophagectomy specimens resected for high-grade dysplasia or early invasive (intramucosal and submucosal) carcinoma. We developed surface area maps and assessed the various degrees of dysplasia or carcinoma at 10 equidistant points. Our analysis shows an equal likelihood of high-grade dysplasia and/or early invasive carcinoma occurring throughout the length of Barrett's epithelium. Foci of carcinoma appear within fields of Barrett's epithelium and adjacent to areas of dysplasia, supporting a dysplasia-carcinoma sequence. The amount of dysplastic epithelium appears related to the surface area of Barrett's epithelium present. However, we found no association between the extent of dysplasia and the likelihood of finding carcinoma. This study supports the current standard of practice for clinical surveillance of patients with Barrett's esophagus by uniformly distributed endoscopic biopsy of the complete length. In addition, the presence of any degree of dysplasia may be an indication for close clinical follow-up.

Effects of 2,3-butanedione monoxime on blood pressure, myocardial Ca2+ currents, and action potentials of rats.

2,3-Butanedione monoxime (BDM) has a negative inotropic effect on smooth muscles as well as the myocardium. Therefore, in the present study we compared the sensitivity to BDM of the cardiovascular system of the spontaneously hypertensive (SHR) and the normotensive Wistar-Kyoto (WKY) rat. While BDM significantly decreased the blood pressure (BP) for both strains, the SHR was significantly more responsive. Specifically, 5, 30, 100, and 200 mg/kg BDM (intravenously) reduced BP of the SHR by 9 +/- 3, 20 +/- 3, 49 +/- 5, and 63 +/- 7 mm Hg, respectively. The same doses of BDM reduced BP of the WKY by 0, 2 +/- 0.4, 18 +/- 3, and 26 +/- 3 mm Hg. The duration of the hypotensive effect of BDM was also greater for the SHR. In vitro, BDM had a greater suppressant effect on the L-type Ca2+ current (ICa(L)) of SHR ventricular myocytes; the IC50 for the suppression of ICa(L) was 17 and 29 mM for SHR and WKY ventricular myocytes, respectively. The beta-adrenergic receptor agonist isoproterenol antagonized the suppressant effect of BDM on ICa(L). Furthermore, BDM significantly reduced the duration of both spontaneous and electrically stimulated action potentials of cultured neonatal rat cardiomyocytes. Intracellular dialysis with the catalytic unit of protein kinase A antagonized BDM's effect on the action potential. These data suggest that suppression of myocardial activity contributes to the hypotensive effect of BDM. In addition, the elevated response to BDM of SHR cardiac myocytes may indicate that the conformation and/or modulation of the L-type Ca2+ channel differ for the SHR and WKY lines of rat.

Use of specimen turnaround time as a component of laboratory quality. A comparison of clinician expectations with laboratory performance.

Quantitative laboratory quality measures include test accuracy and precision. To be useful, however, tests also must be available in a timely manner. The authors surveyed 757 University of California, Los Angeles, house officers (485-64% responded) regarding their expectations of laboratory test turnaround time for five test groups that are regularly offered both stat and routine. They compared expectations with actual laboratory performance by evaluating turnaround time for 42,414 consecutive laboratory requests received over two weeks. The authors' laboratory performed 45% of studied analytes stat. Median turnaround time was 44 minutes for stat and 119 minutes for routine tests, although variation exists by test group. The percentage of time their laboratory met median stat and routine turnaround time expectations varies by shift and work area. Timeliness of results often may be as important as accuracy and precision in assuring quality of care and cost-effective use of hospital services. Although the laboratory may not meet current housestaff turnaround time expectations, it is unclear whether laboratory performance is inadequate or housestaff expectations are unreasonable. Publicizing actual routine turnaround times may reduce the number of stat requests ordered if routine turnaround times are incorrectly perceived to be too slow. Reduction in stat test ordering may improve overall laboratory performance and turnaround time. The authors recommend that clinical pathologists and clinicians together develop turnaround time goals based on practicality, medical necessity, and clinician expectations.

Evaluation of stat and routine turnaround times as a component of laboratory quality.

Quality assurance has been an essential part of clinical laboratory operations for more than two decades. Analytic precision and accuracy goals have been established, and laboratory performance is monitored periodically. For a laboratory test to be useful, it must be available in a timely manner. Expedience of result reporting has not, however, been routinely included among measures of laboratory quality. The authors evaluated stat and routine turnaround times for 42,414 requests on 24 clinical analytes over a 14-day period with the use of a personal computer. Median turnaround time is 1.70 times faster for stat than for routine tests. When examined by shift, average turnaround time is considerably faster for tests ordered stat than for tests ordered routinely during the day and evening shifts, when the work load is the greatest. The authors are now examining turnaround time as an indicator of quality laboratory performance and efficiency. Computer systems in many clinical laboratories already have the sophistication necessary to perform turnaround time analysis. The authors recommend that clinical laboratories begin to include timeliness of stat and routine result reporting as part of their quality assurance programs. Laboratories may also wish to investigate the usefulness of stat requests during slower shifts because these requests may interrupt the normal flow of specimens without expediting result reporting.

Ergotism: a possible etiology for puerperal psychosis.

Some reports in the medical literature have mentioned the occurrence of psychotic reactions in response to the use of certain ergot alkaloids in therapeutic doses. Prompted by these observations, we undertook a search for cases of "pure" puerperal psychosis (ie, typical manifestations 3-14 days postpartum) in order to evaluate the clinical background of this phenomenon. Special attention was paid to the medications that the patients had received peripartum. In the last 10 years, out of eight perinatal centers, we found only three cases that fulfilled the criteria of the quoted entity. In all instances, the manifestations of puerperal psychosis had been preceded by the administration of ergot derivatives. Based on the presented data, we hypothesize that typical postpartum psychosis may represent an idiosyncratic reaction to potent vasoactive drugs including ergot derivatives. The similarities between the clinical manifestations of ergotism and puerperal psychosis, and some of the epidemiologic features of the latter condition, appear to implicate ergot alkaloids as potential causative agents. Although the validity of the suggested interpretation requires further evaluation, we believe that the currently available data warrant caution with regard to the administration of ergot derivatives postpartum. These drugs should not be used in the absence of clear indication or in unnecessarily high doses. We suggest that ergotism be included in the differential diagnosis in cases of pure puerperal psychosis.

Sporadic primary hyperparathyroidism in the setting of multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant disease characterized by neoplasia involving the parathyroid glands, the endocrine pancreas, the duodenum, and the anterior pituitary. The most commonly involved gland is the parathyroid gland, which has been found to be abnormal in 90% to 95% of all patients with MEN 1. The disease process is invariably multiglandular and histologically described as either hyperplasia or multiple adenoma, although the histological distinction between the 2 entities remains difficult and controversial. The prevalence of MEN 1 is approximately 0.002 in 100, whereas the prevalence of sporadic primary hyperparathyroidism due to a solitary adenoma is estimated to be as high as 1 in 100.(2.3) We report herein the first case of sporadic primary hyperparathyroidism in the setting of MEN 1 based on clinical, biochemical, pathological, and genetic studies.

Cause of death in multiple endocrine neoplasia type 1.

OBJECTIVE: Little data are available on the natural history of untreated multiple endocrine neoplasia type 1 (MEN-1). These data are essential in deciding treatment that may carry significant morbidity. We determined the causes of death in a large MEN-1 kindred with data available over a period of 130 years. Most cases were unrecognized as MEN-1 at the time of patient's death. DESIGN: Retrospective study of recorded medical data from 1861 to 1991. PATIENTS: One hundred fifty-nine deaths occurred, of which 46 were in individuals classified as "highly probable" of having MEN-1. RESULTS: Of 46 deaths in those classified as "highly probable" of having MEN-1, 20 (43.5%) died of a recognized complication of MEN-1 (12 of malignant neoplasms, six of renal calculi, and two of peptic ulcer). If accidental deaths are excluded, 50% of the deaths in patients with MEN-1 were the result of MEN-1, and the mean age of death (50.9 years)was significantly younger than that of other family members. CONCLUSIONS: It is concluded that MEN-1 leads to premature death, and that neoplasia rather than peptic ulcer disease is the main cause of death. Deaths from pituitary tumor or malignant endocrine tumors within the thorax were just as common or more common than deaths from pancreatic malignant neoplasms.