Lower initial dose desoxycorticosterone pivalate for treatment of canine primary hypoadrenocorticism.

OBJECTIVE: To evaluate the efficacy of initial doses of desoxycorticosterone pivalate (DOCP) that are lower and less expensive than the presently recommended initial dose of 2.2 mg/kg for treating dogs with primary hypoadrenocorticism. METHODS: A retrospective study was performed on 49 dogs with primary hypoadrenocorticism, including 36 with initial DOCP doses less than 2.2 mg/kg. Medical records were reviewed for clinical data. All study dogs were followed up with telephone calls to owners or veterinarians to determine the date of death or last follow-up. Data were analysed to investigate relationships between initial DOCP dose and survival and serum Na, K and their ratio. RESULTS: Regardless of their initial DOCP dose, none of the dogs developed uncontrolled hypoadrenocorticism or severe electrolyte abnormalities or clinical problems that would have made an increase in the DOCP dose necessary. Over time, most dogs had a decrease in their DOCP dose in mg/kg, because of weight gain during treatment. No statistically significant relationships were found between initial DOCP dose and survival or post-treatment serum Na, K or Na : K, with the exception of one statistically significant result that suggested lower efficacy for higher doses. CONCLUSION: Initial DOCP doses less than 2.2 mg/kg may be effective in controlling serum electrolyte concentrations in dogs with primary hypoadrenocorticism without adversely affecting survival. If confirmed by additional research, these findings would enable practitioners to reduce the cost of DOCP treatment by using lower initial doses, potentially saving the lives of dogs that would otherwise be euthanased because of treatment expense.

The application of real-time PCR to the identification, detection and quantification of Pyrenophora species in barley seed.

Summary A real-time quantitative PCR technique has been used to develop a rapid and sensitive seed health test for Pyrenophora spp. on barley seed. Using the fluorescent reporter dye SYBR Green I for real-time detection of PCR amplification, pathogen DNA extracted from infected seed can be quantified to the picogram level. The amount of Pyrenophora DNA extracted from seed samples of an artificial infection level gradient, constructed by mixing infected and uninfected seed, correlated with good agreement (r = 0.931) to percentage infection levels of the same samples measured by agar plate testing. In addition, a correlation of r = 0.883 was obtained between the two testing methods for naturally infected seed, ranging from 0% to 89% infection. Samples could be quantified to below the 2% voluntary threshold required for deciding on seed treatment. The proposed test was performed in three parts: (i) quantification of Pyrenophora spp. infection using Pyrenophora-specific PCR primers; (ii) test of any negative samples from (i) with barley-specific PCR primers to check the DNA extraction process; (iii) test of positive samples from (i) for the presence of Pyrenophora graminea using P. graminea-specific PCR primers. All PCRs were performed in the LightCycler instrument allowing each PCR run and analysis to be completed within 30 min. With the current daily receipt of samples (batches up to 16) the test can be completed in 8 h, compared to 7 days for the traditional agar plate test.

Scorpion ARMS primers for SNP real-time PCR detection and quantification of Pyrenophora teres.

summary We have developed a quantitative PCR detection method that can be used to determine the seed infection levels of Pyrenophora teres, a seed-borne fungal pathogen of barley. This method uses Scorpion Amplified Refractory Mutation System (ARMS) technology with real-time PCR detection. Scorpion ARMS primers were designed and optimized such that a single nucleotide base mismatch in the primer sequence could distinguish P. teres from P. graminea, a closely related seed-borne pathogen of barley. It is necessary to distinguish between these two agriculturally important pathogens since different disease management decisions are made, based on the presence and level of infection measured for each. The advance in development of sensitive and specific fluorescent probes has enabled the current PCR test to detect Pyrenophora spp. pathogenic on barley to be enhanced with the advantage that it can now specifically detect P. teres in a single reaction, whilst previously, two reactions were required to discriminate P. teres from P. graminea.

Neuropsychology of first-episode schizophrenia: initial characterization and clinical correlates.

OBJECTIVE: Neuropsychological impairments are well documented in schizophrenia and are important targets of treatment. Information about the severity and pattern of deficits after treatment for the first psychotic episode and about relationships between these deficits and syndromal characteristics remains limited. METHOD: Comprehensive neuropsychological assessments including 41 individual tests were given to 94 patients with first-episode schizophrenia after initial stabilization of psychosis and to a comparison group of 36 healthy volunteers. Profiles of neuropsychological deficits and the relationship of deficits to sex and handedness were examined. Correlations of neuropsychological deficit with a broad range of historical and clinical characteristics, including outcome, were explored. RESULTS: Patients had a large generalized neuropsychological deficit (1.5 standard deviations compared to healthy volunteers). Patients also had, superimposed on the generalized deficit, subtle relative deficits (less than 0.5 standard deviation compared to their own average profile) in memory and executive functions. Learning/memory dysfunction best distinguished patients from healthy individuals; after accounting for this difference, only motor deficits further distinguished the groups. Patients with higher neuropsychological ability had only memory deficits, and patients with lower ability had both memory and executive deficits. No sex differences were observed beyond the normal advantage for men in motor speed. Dextral patients had less severe generalized deficit. Severity of residual symptoms was associated with greater generalized deficit. Executive and attentional deficits were most linked to global functional impairment and poor outcome. CONCLUSIONS: The results document a large generalized deficit, and more subtle differential deficits, in clinically stabilized first-episode patients. Learning/memory deficits were observed even in patients with less severe generalized deficit, but the pattern was unlike the amnestic syndrome and probably reflects different mechanisms. Executive and attentional deficits marked the more severely disabled patients, and may portend relatively poor outcome. Failure to develop typical patterns of cerebral dominance may increase the risk for greater generalized deficit.

Role of intracellular sodium overload in the genesis of cardiac arrhythmias.

A number of clinical cardiac disorders may be associated with a rise of the intracellular Na concentration (Na(i)) in heart muscle. A clear example is digitalis toxicity, in which excessive inhibition of the Na/K pump causes the Na(i) concentration to become raised above the normal level. Especially in digitalis toxicity, but also in many other situations, the rise of Na(i) may be an important (or contributory) cause of increased cardiac arrhythmias. In this review, we consider the mechanisms by which a raised Na(i) may cause cardiac arrhythmias. First, we describe the factors that regulate Na(i), and we demonstrate that the equilibrium level of Na(i) is determined by a balance between Na entry into the cell, and Na extrusion from the cell. A number of mechanisms are responsible for Na entry into the cell, whereas the Na/K pump appears to be the main mechanism for Na extrusion. We then consider the processes by which an increased level of Nai might contribute to cardiac arrhythmias. A rise of Na(i) is well known to result in an increase of intracellular Ca, via the important and influential Na/Ca exchange mechanism in the cell membrane of cardiac muscle cells. A rise of intracellular Ca modulates the activity of a number of sarcolemmal ion channels and affects release of intracellular Ca from the sarcoplasmic reticulum, all of which might be involved in causing arrhythmia. It is possible that the increase in contractile force that results from the rise of intracellular Ca may initiate or exacerbate arrhythmia, since this will increase wall stress and energy demands in the ventricle, and an increase in wall stress may be arrhythmogenic. In addition, the rise of Na(i) is anticipated to modulate directly a number of ion channels and to affect the regulation of intracellular pH, which also may be involved in causing arrhythmia. We also present experiments in this review, carried out on the working rat heart preparation, which suggest that a rise of Na(i) causes an increase of wall stress-induced arrhythmia in this model. In addition, we have investigated the effect on wall stress-induced arrhythmia of maneuvers that might be anticipated to change intracellular Ca, and this has allowed identification of some of the factors involved in causing arrhythmia in the working rat heart.

Inhibition by external Cd2+ of Na/Ca exchange and L-type Ca channel in rabbit ventricular myocytes.

We investigated the effect of external Cd2+ on the Na/Ca exchange and the L-type Ca channel current (ICa,L) in whole cell patch-clamped rabbit ventricular myocytes at 36 degrees C. After the interfering ion channels and the Na/K pump were blocked, the exchange current was measured as the membrane current that was inhibited by 5 mM nickel. External Cd2+ inhibited Na/Ca exchange with a dissociation constant (KD) of 320.6 +/- 12.4 microM and a Hill coefficient of 1.5 +/- 0.09 (n = 13 cells) and ICa,L with a KD of 2.14 +/- 0.15 microM and a Hill coefficient of 0.74 +/- 0.03 (n = 11 cells). We observed some overlap in the Cd2+ concentration that blocked each mechanism. Cd2+ (100-500 microM) is used commonly to block ICa,L completely. However, 100 microM Cd2+ also inhibits 20% of the Na/Ca exchange activity, whereas 500 microM Cd2+ inhibits 60%.

Differentiation of growth retarded from normally grown fetuses and prediction of intrauterine growth retardation using Doppler ultrasound.

OBJECTIVE: To assess the hypothesis that infants exhibiting catch-up growth as an indicator of intrauterine growth retardation (IUGR) have a higher incidence of predelivery abnormal Doppler results. SETTING. Obstetric unit, St James's University Hospital, Leeds. PARTICIPANTS: One hundred and ninety-six women with singleton pregnancies at high risk of IUGR, delivered between October 1992 and August 1993. MAIN OUTCOME MEASURES: Postnatal catch-up growth during the first seven months. RESULTS: Forty-six of the 196 infants demonstrated catch-up growth and were therefore classified as growth retarded; 85% of this group had had abnormal Doppler results prior to delivery, compared with 14% of the normally grown group. However, there is considerable overlap in birthweight ratio distribution between the two groups. CONCLUSION: This study confirms the existence of a population of IUGR infants of average birthweight ratio. Doppler appears to distinguish IUGR (as defined by catch-up growth) from normal growth more successfully in infants with an average birthweight ratio than in infants with a low birthweight ratio and is a better predictor of IUGR than SGA.

An audit of the role of the sonographer in non-obstetric ultrasound.

In order to investigate the role of the sonographer in non-obstetric ultrasound, 1046 consecutive non-obstetric ultrasound scans performed by sonographers were audited. In 94% of cases, the report prepared by the sonographer gave an accurate account of the findings. In 6.3% of reports the radiologist provided additional comments, whilst in only 0.7% of cases was the sonographer's report significantly altered. In the 630 patients in whom adequate follow-up data was available, there was a single instance of a false positive ultrasound finding but no other significant ultrasound inaccuracy. This audit indicates that the local arrangements for involving sonographers in a non-obstetric ultrasound service has resulted in agreed standards being met. It is suggested that sonographers can and should be involved more widely in the provision of non-obstetric ultrasound services.

Evaluation of two opioid-acetaminophen combinations and placebo in postoperative oral surgery pain.

STUDY OBJECTIVE: To determine the relative analgesic potency and adverse effect liability of hydrocodone bitartrate 7.5 mg with acetaminophen 500 mg, codeine phosphate 30 mg with acetaminophen 300 mg, and placebo in the treatment of pain following oral surgery. DESIGN: Randomized, double-blind, single-dose, placebo-controlled, parallel-group study with self-ratings at 30 minutes and then at hourly intervals from hour 1 to hour 6. SETTING: Private, oral surgery practice sites. PATIENTS: Three hundred twenty-four outpatients with moderate or severe pain after the surgical removal of impacted third molars were selected. One was lost to follow-up and 32 did not need an analgesic; 232 patients had valid efficacy data. INTERVENTIONS: Patients were treated with a single oral dose of hydrocodone bitartrate 7.5 mg with acetaminophen 500 mg, codeine phosphate 30 mg with acetaminophen 300 mg, or placebo when they experienced steady, moderate or severe pain that, in their opinion, required an analgesic. Using a self-rating record, subjects rated their pain and its relief for 6 hours after medicating; estimates of peak and total analgesia were derived from these subjective reports. MEASUREMENTS AND MAIN RESULTS: This study was a valid analgesic assay. Both active treatments were significantly superior to placebo for all measures of analgesic efficacy. The hydrocodone-acetaminophen combination was significantly superior to the codeine-acetaminophen combination for total pain relief and the number of evaluations with 50% relief. Both active treatments manifested an analgesic effect within 30 minutes; the effect persisted for 5 hours for the codeine combination and 6 hours for the hydrocodone combination. Adverse effects were transient, consistent with the pharmacologic profiles of opioids, and none required treatment. CONCLUSIONS: A slight advantage in analgesic efficacy was demonstrated in this single-dose study for the hydrocodone-acetaminophen combination. Repeat-dose studies, however, should be conducted to determine the clinical significance of the difference in analgesic effect of these opioid combinations.

Reproducibility of Doppler ultrasound measurement of resistance index in renal allografts.

In recent years measurements of arterial blood flow in the renal allograft have been studied in an attempt to provide a non-invasive method of diagnosing and monitoring post-transplant renal dysfunction. Many studies have involved measurement of the resistance index (RI) of arterial blood flow. Although the reproducibility of the technique has been studied in other areas of application, no such studies have been performed on the renal allograft. In this study we attempted to evaluate the reproducibility of the measurement of the RI of the interlobar artery in the renal allograft. 18 renal allograft recipients with stable functioning grafts were studied twice by each of two experienced sonographers using a colour-coded duplex Doppler ultrasound scanner, in order to determine the intraobserver and interobserver variability in the measurement of RI of the interlobar arteries in the allograft. Variability was small and although interobserver variability exceeded intraobserver variability, both were within repeatability limits adopted by the British Standards Institution. The results suggest that measurement of the RI of the interlobar artery of renal allografts is repeatable and reproducible when performed by experienced operators.

Monitoring renal allograft rejection with duplex sonography.

Thirty-six renal allograft recipients were monitored by serial duplex Doppler ultrasound studies post-transplant and during early rejection. A separate reproducibility study demonstrated no significant inter- or intra-operator variability in measurements of resistive index of an interlobar artery (RI) (2.1% [1.5%] and 3.2% [2.3%] respectively, mean [standard error] of coefficients of variance). Twenty-one patients had rejection within 3 weeks of transplantation. These grafts showed greater overall rises in the RI, from day 2 to day 5 post-transplant, than the grafts which had no rejection. Eleven of the 21 patients required more than one course of methyl-prednisolone for persistent or recurring rejection. These grafts had higher RI on the day rejection was diagnosed (81 [7.3], median [interquartile range]) compared with the remaining 10 patients (68.6 [8.7]). The 11 grafts with persistent rejection had higher RI (p less than 0.005, Mann-Whitney U-test) on day 2 post-transplant (76 [3.9]) compared with the 10 grafts successfully treated with a single course of methyl-prednisolone (63.2 [10.9]). This study demonstrates that grafts with an RI of greater than 70 on day 2 post-transplant are likely to have rejection requiring additional treatment (sensitivity--100%, specificity--80%). These patients may be candidates for earlier or alternative anti-rejection therapy.

Inability of color and spectral Doppler to identify fetal renal obstruction.

Color flow Doppler imaging was used to obtain fetal renal artery flow velocity waveforms in 130 normal fetuses at various gestational ages to build a database for the establishment of normal ranges for the Pulsatility Index in the fetal renal arteries throughout pregnancy. Twenty-nine cases of fetal renal tract dilation (greater than 5 mm anteroposterior diameter of the renal pelvis) of various causes were investigated. We found that measurements of the pulsatility index were not significantly altered from the normal range, so that color flow Doppler does not appear to be helpful in the differential diagnosis of fetal renal dilation.

Intrarenal Doppler ultrasound studies in normal and acutely obstructed kidneys.

Renal ultrasound examinations and intrarenal arterial Doppler studies were performed on 48 patients with normal renal tracts and 20 patients presenting with acute renal colic resulting from ureteric calculus, 14 of whom had urographic evidence of renal obstruction. The mean resistance index (RI) of the Doppler waveforms obtained on the 14 obstructed kidneys (70.4 +/- 6.22) was significantly higher than the mean RI of the 96 normal kidneys (62.4 +/- 6.43). The mean difference between the RIs of the obstructed kidneys and their contralateral non-obstructed kidneys (8.37 +/- 4.43) was also significantly higher than the differences in RI seen between pairs of normal kidneys (2.70 +/- 1.71). Five out of 14 obstructed kidneys showed no pelvicalyceal dilatation and could not have been shown to be obstructed on conventional sonography. Four of these five had RI changes suggestive of obstruction and thus 13 of 14 obstructed kidneys would have been identified as obstructed by a combination of Doppler and conventional sonographic findings. 10 of the 14 obstructed kidneys were re-examined after passage of a urinary calculus and nine showed a reduction in the RI of the previously obstructed kidneys. The 10th subsequently required ureterolithotomy.

Revolving drug funds: conducting business in the public sector.

Pharmaceuticals are essential for preventive and therapeutic health services. Unfortunately, significant demand, limited funds and high prices contribute to frequent shortages of drugs in many public health programs. One method for financing pharmaceutical supplies has been the establishment of revolving drug funds (RDFs) in which, after an initial capital investment, drug supplies are replenished with monies collected from the sale of drugs. All too often however, the funds actually recovered are insufficient to replenish supplies and the fund is soon depleted. In this paper we consider the potential benefits and common pitfalls of revolving drug funds and then focus on the central role of financial planning in establishing drug sales programs. Experiences from a variety of countries suggest several causes for the failure of some RDFs, including: under-estimation of capitalization costs, prices set below true replacement cost, frequent failure to collect payment, delays in cash flow which make funds unavailable for replenishment of drug stocks, rapid program expansion for which additional capital funds are not available, losses due to theft and deterioration of drugs, unanticipated price increases due to inflation or changes in parity rates and foreign exchange purchase restrictions. Common to many of these problems is the lack of a businesslike orientation to RDFs and, in particular, lack of careful financial planning and management. Financial planning for an RDF includes four analytical tasks: assessment of the potential market, estimation of the costs of an RDF, establishment of the cost-recovery objectives, definition of the role of subsidies and surcharges.(ABSTRACT TRUNCATED AT 250 WORDS)

Transcutaneous electrical nerve stimulation for chronic pain.

The results of 7 years experience in treating pain with transcutaneous electrical stimulation are reported. It was used on a group of 74 patients with postherpetic neuralgia and on a mixed group of 161 patients with chronic pain due to other conditions for which other forms of treatment had been unsatisfactory. The patients were lent stimulators and electrodes of various kinds. A half of the patients returned their stimulators after one month, but a quarter of the patients were still using transcutaneous stimulation after 2 years. No particular disease responded better or less well than any other; no particular kind of pain responded particularly well or badly. One third of the patients with postherpetic neuralgia started improving from the commencement of stimulation.

Therapeutic electrical stimulation. The transistorized placebo?

(1) Electrical stimulation therapy for patients suffering with labile signs and symptoms, and these include all varieties of acute and chronic pains, seizures and spasticity, has come into fashion and gone, and come again with each new technological advance for the past two hundred years. (2) A proportion of patients with chronic disease have their suffering made worse if they feel deprived of the latest therapy and may be relieved if they are given it in the right circumstances. In this group the relief will usually be temporary and the limited supply of such reactors will promote the cycle of fashion. In a group of 126 patients with chronic pain associated with organic disease who were offered transcutaneous stimulation, only 23 (18%) continued to use it one year after they started. (3) The cycling of therapeutic fashion is assisted not only because relief is often temporary, but also by the difficulty in establishing the normal range of variability from which significant change can be assessed and by the uncertain relationship between signs and symptoms and for the functions of daily living. For these reasons there is an inevitable tendency to temporary over-optimism and it seems impossible to counter this by the execution of a satisfactory clinical trial, since the patient cannot be "blind" and a significant variable is the enthusiasm with which a therapy is surrounded. (4) Electrical stimulation by cutaneous devices or implants can give much benefit to some patients in whom other methods have failed and there are indications, not only from anecdote and clinical impression but also now from experimental physiology, that it may benefit by mechanisms of interaction at the first sensory synapse. It is, however, an over-simplification to regard any therapy as either strictly physiological or simply fraudulent. Like other so-called placebos, physical methods of therapy can presumably act on hormonal systems associated with stress and the experience of pain.