Evaluation of the hypothalamic-pituitary-adrenal axis in patients with antiphospholipid syndrome.

INTRODUCTION: Hypothalamic-pituitary-adrenal (HPA) axis insufficiency is the most common endocrine disorder in patients with antiphospholipid syndrome (APS). Primary adrenal failure because of venous thrombosis and/or adrenal haemorrhage is the leading diagnosis, while another possible mechanism is autoimmune adrenal failure. Prospective evaluation of the HPA axis in patients with APS has not been previously performed. AIMS: To evaluate the HPA axis in patients with APS. METHODS: Ambulatory patients (age 18 years and older) with APS were given a symptom questionnaire. Baseline aldosterone, corticotropin (ACTH) and adrenal cortex autoantibodies (ACA) were measured. Cortisol was measured at baseline and after 1-mcg ACTH stimulation. RESULTS: In all, 24 patients (18 women/6 men; mean age 44.6 +/- 16.1 years) participated in the study. Of these, 21 had primary APS with disease duration of 5.8 +/- 6.2 years. Baseline cortisol level was 12.6 +/- 4.2 mg/dl (normal 7-25). After ACTH stimulation, it was 24.7 +/- 4.1 mg/dl and 22.8 +/- 7.4 mg/dl at 30 and 60 min respectively. All patients had a stimulated cortisol level of at least 18 mg/dl, although three patients had stimulated cortisol between 18 and 20 mg/dl, one of which reported previous inhaled steroid treatment. Weakness, dizziness and nausea were reported at baseline by 50%, 38% and 25% of the patients respectively. ACA were negative in all patients examined. CONCLUSIONS: In our cohort, patients with APS did not have HPA axis insufficiency. Partial adrenal insufficiency could not be excluded in two patients. Further longitudinal studies are needed to determine the significance of periodic evaluation of the HPA axis in patients with APS.

Cardiac troponin T is not increased in patients with hypothyroidism.

Patients with hypothyroidism often have increased creatine kinase (CK) levels. It is possible that there is increased production of CK, but other mechanisms, such as an increased cell membrane permeability or decreased enzyme clearance were also proposed. Recently, troponins T and I have been extensively studied because of their cardiac specificity. Cardiac troponins are sensitive and specific markers of cardiac injury. The objective of the study was to measure cardiac troponin T (cTnT) levels in patients with hypothyroidism. Twenty-five patients with primary hypothyroidism were evaluated (thyroid-stimulating hormone (TSH) >30 mU/L and low FT(4)). In all patients thyrotropin (TSH), free thyroxine (FT(4)), CK, CK-MB and cTnT were measured.There were 3 men and 22 women with a mean age of 47.5 +/- 12.4 years. TSH levels ranged from 31 to 75 mIU/L and mean FT(4) levels were 4.5 +/- 1.9 pmol/L. CK was normal in 11 patients and increased in 14. CK levels ranged between 86 and 1221 U/L (normal levels <170 in women, <195 in men) with a mean of 322 U/L +/- 279. CK-MB was increased in 4 patients (16%) and normal in 21. All 25 patients had normal cTnT levels, < 0.01 ng/mL (normal levels 0-0.1 microg/L). Increase in CK and its MB fraction are common in patients with hypothyroidism but cTnT levels are not, even in patients with increased CK-MB. Therefore, cTnT is a reliable marker of cardiac injury even in the hypothyroid patient.

Clinical relevance of non-palpable thyroid nodules as assessed by ultrasound-guided fine needle aspiration biopsy.

It is known from autopsy data that thyroid nodules are far more common than can be detected by palpation alone. With the wide use of modern non-invasive imaging many non-palpable thyroid nodules are discovered but the proper approach to these nodules is still debatable. In a retrospective study, we reviewed the data from 186 US-guided FNA biopsies (US-FNAB) performed between May 1995 and March 1997 at the Sapir Medical Center, Israel, a iodine-sufficient urban area. Sixty-one of the 186 US-FNAB of the thyroid were performed in non-palpable nodules. The mean size of these nodules was 2.4 +/- 1.0 cm (mean +/- SD) ranging from 1.1-5.5 cm. Description of the nodule consistency was available in 53 cases; 42/53 were solid and 11/53 were solid-cystic. FNAB was diagnostic in 46 patients and non-diagnostic in 15. Forty-three of the diagnostic cytology reports were benign, one revealed papillary carcinoma, one had suspicious findings and the third was suspicious for a follicular neoplasm. The last two patients were referred to surgery and a follicular adenoma was found in both. Among the 61 non-palpable thyroid nodules, only one was papillary carcinoma, a prevalence of 1.6%. The other two patients referred to surgery had benign lesions. We found a low prevalence of malignancy in relatively large non-palpable thyroid nodules.

Quality of life assessment in elite collegiate athletes.

The objectives of this study were to establish baseline Medical Outcomes Study Short Form Health Survey (SF-36) data for Division I collegiate athletes and to determine the effects of injury severity and training time. All participating athletes (N = 562) at a major university were evaluated with the SF-36. Regression analysis was performed to identify predictive factors. When the men without injury were compared with a previously established norm group, there was a significant increase in the role emotional score. In the women without injury there were significant increases in mental component summary, physical function, role emotional, mental health, and vitality scores when compared with the norm group. Serious injury was a predictor of lower scores in all domains, whereas minimal injury was predictive of lower physical component summary, role physical, bodily pain, social function, and general health scores. Increased training time was predictive of higher mental component summary, role physical, vitality, and general health scores. Elite collegiate athletes scored differently from previously established age-matched norms, and injury was a strong predictor of lower scores.

Efficacy of nonoperative treatment for lateral epicondylitis.

One hundred cases of lateral epicondylitis among 97 patients were reviewed, and 84 patients were contacted for long-term follow-up. Patients participated in a structured nonoperative treatment regimen. Mean age of contacted patients was 49 years; mean follow-up was 2.8 years. Surgery was averted in 65 (75%) of 87 cases. Patients who achieved pain control after only 1 cortisone injection successfully avoided surgery 88% of the time, whereas those requiring multiple injections avoided surgery only 44% of the time. Eventual outcomes were similar, regardless of treatment type. Patients requiring multiple cortisone injections to alleviate acute pain have a guarded prognosis for continued nonoperative management.

Identification of subtypes of muscarinic receptors that regulate Ca2+ and K+ channel activity in sympathetic neurons.

Many different G protein-coupled receptors modulate the activity of Ca2+ and K+ channels in a variety of neuronal types. There are five known subtypes (M1-M5) of muscarinic acetylcholine receptors. Knockout mice lacking the M1, M2, or M4 subtypes are studied to determine which receptors mediate modulation of voltage-gated Ca2+ channels in mouse sympathetic neurons. In these cells, muscarinic agonists modulate N- and L-type Ca2+ channels and the M-type K+ channel through two distinct, G-protein mediated pathways. The fast and voltage-dependent pathway is lacking in the M2 receptor knockout mice. The slow and voltage-independent pathway is absent in the M1 receptor knockout mice. Neither pathway is affected in the M4 receptor knockout mice. Muscarinic modulation of the M current is absent in the M1 receptor knockout mice, and can be reconstituted in a heterologous expression system using cloned channels and M1 receptors. Our results using knockout mice are compared with pharmacological data in the rat.

Quantitative tests of an associative theory of risk-sensitivity in honeybees.

Risk-sensitivity was studied in free-flying honeybees trained individually to choose between two scented targets (A and B) with varying amounts and concentrations of sucrose solution as reward. In the first phase of experiment 1, the animals showed "risk-aversion," preferring A, which provided 5 microl of a 40 % sucrose solution on every trial, to B, which provided 30 microl of the same solution once in every six trials (mean amount per trial 5 microl for each alternative). In the second phase, the preference reversed with reversal of the reward assignments. In experiment 2, the consistently rewarded A (5 microl of 40 % sucrose solution per trial) was again preferred, although the inconsistently rewarded B now provided twice the amount of sucrose solution on average (30 microl on two of every six trials, mean amount per trial 10 microl). In experiment 3, with A providing 10 microl of a 15 % sucrose solution on every trial and B providing 10 microl of a 60 % sucrose solution on two of every four trials (mean concentration per trial 30 %), the animals preferred B. In Experiment 4, patterned after experiment 1, similar results were obtained under more natural conditions in which the animals were no longer constrained (as they were in the first three experiments) to go equally often to each alternative. The results of all four experiments were predicted quantitatively and with considerable accuracy by a simple associative theory of discriminative learning in honeybees.

Colonic perforation in unsuspected amebic colitis.

Unsuspected amebic colitis presenting as inflammatory bowel disease, as in our patient, has been previously reported (4, 7, 8). Misdiagnosis, delay in antibiotic treatment, and institution of immunosuppression were the result of failure to identify the parasite in stool specimens and have resulted in suffering, morbidity, mortality, and surgery. In all previously reported cases, routine stool studies failed to identify E. histolytica (4, 7, 8). The correct diagnosis was only established after reviewing the surgical specimen or biopsies obtained endoscopically. Because the erroneous diagnosis of inflammatory bowel disease can lead to disastrous complications, it is imperative to exclude amebic colitis prior to undertaking steroid therapy, especially in patients with a prior history of travel to or residence in areas with endemic E. histolytica (17). We recommend obtaining at least three stool specimens for microscopic examination, as well as testing for serum amebic antibody. Patients should submit fresh stool specimens directly to the laboratory to allow for prompt diagnostic evaluation. Such an approach might lead to the improved diagnosis of amebiasis.

Parental assessment of behavior in Chinese adoptees during early childhood.

The Parent Rating Scale of the Behavior Assessment Scale for Children (PRS-BASC) was used to examine the behavior of 45 Chinese adoptees. In all but one case, results from the 9 BASC-PRS scales ranged in the average, or normal, range. Thus, as a group, no deviations from normal behavior were revealed. However, the variability of ratings for several scales--Hyperactivity, Aggression, Conduct Problems, and Attention Problems--indicated a greater potential for at-risk behavior. Age of adoption from China was not a significant influence on parents' perceptions of adoptees' behavior. However, older adoptees were more likely to be rated hyperactive or aggressive than younger children, while younger adoptees were more likely to exhibit withdrawal.

The relationship between acromial morphology and conservative treatment of patients with impingement syndrome.

This study assessed the predictive value of acromial morphology in the treatment outcome of patients with impingement syndrome. Sixty-five patients with impingement syndrome were treated by a single orthopedic surgeon according to the same protocol and initially received the same conservative modalities. The incidence of acromial types in the nonoperative group was significantly different from those in the operative group (P=.008). A large proportion (88.9%) of the patients with type I acromions responded to conservative measures, while fewer (73.1%) patients with type II acromions responded to conservative measures. The majority (58.3%) of patients with type III acromions required surgical intervention. Acromial morphology appears to have a predictive value in determining the success of conservative measures and the need for surgery in patients with impingement syndrome.

Quantitative analysis of risk sensitivity in honeybees (Apis mellifera) with variability in concentration and amount of reward.

Free-flying honeybees (Apis mellifera) were trained in a series of experiments designed to look for evidence of risk sensitivity in foraging for sucrose solution. The suitability of the choice method used was established in 3 preliminary experiments with differences in concentration, amount, and probability of reward. Of 5 subsequent experiments in which 2 alternatives provided the same mean concentration of sucrose solution with different variance, 3 showed risk indifference, and 2 showed risk aversion (preference for consistent reward). Of 2 final experiments in which the alternatives provided the same mean amount of sucrose solution with different variance, both showed risk aversion. Performance could be simulated quantitatively with a simple choice model developed by P. A. Couvillon and M. E. Bitterman (1991) to account for the results of a wide range of previous experiments on discriminative learning in honeybees.

Structural basis for ligand selectivity of heteromeric olfactory cyclic nucleotide-gated channels.

In vertebrate olfactory receptors, cAMP produced by odorants opens cyclic nucleotide-gated (CNG) channels, which allow Ca(2+) entry and depolarization of the cell. These CNG channels are composed of alpha subunits and at least two types of beta subunits that are required for increased cAMP selectivity. We studied the molecular basis for the altered cAMP selectivity produced by one of the beta subunits (CNG5, CNCalpha4, OCNC2) using cloned rat olfactory CNG channels expressed in Xenopus oocytes. Compared with alpha subunit homomultimers (alpha channels), channels composed of alpha and beta subunits (alpha+beta channels) were half-activated (K(1/2)) by eightfold less cAMP and fivefold less cIMP, but similar concentrations of cGMP. The K(1/2) values for heteromultimers of the alpha subunit and a chimeric beta subunit with the alpha subunit cyclic nucleotide-binding region (CNBR) (alpha+beta-CNBRalpha channels) were restored to near the values for alpha channels. Furthermore, a single residue in the CNBR could account for the altered ligand selectivity. Mutation of the methionine residue at position 475 in the beta subunit to a glutamic acid as in the alpha subunit (beta-M475E) reverted the K(1/2,cAMP)/K(1/2,cGMP) and K(1/2, cIMP)/K(1/2,cGMP) ratios of alpha+beta-M475E channels to be very similar to those of alpha channels. In addition, comparison of alpha+beta-CNBRalpha channels with alpha+beta-M475E channels suggests that the CNBR of the beta subunit contains amino acid differences at positions other than 475 that produce an increase in the apparent affinity for each ligand. Like the wild-type beta subunit, the chimeric beta/alpha subunits conferred a shallow slope to the dose-response curves, increased voltage dependence, and caused desensitization. In addition, as for alpha+beta channels, block of alpha+betaCNBRalpha channels by internal Mg(2+) was not steeply voltage-dependent (zdelta approximately 1e(-)) as compared to block of alpha channels (zdelta 2.7e(-)). Thus, the ligand-independent effects localize outside of the CNBR. We propose a molecular model to explain how the beta subunit alters ligand selectivity of the heteromeric channels.

Reconstitution of muscarinic modulation of the KCNQ2/KCNQ3 K(+) channels that underlie the neuronal M current.

Channels from KCNQ2 and KCNQ3 genes have been suggested to underlie the neuronal M-type K(+) current. The M current is modulated by muscarinic agonists via G-proteins and an unidentified diffusible cytoplasmic messenger. Using whole-cell clamp, we studied tsA-201 cells in which cloned KCNQ2/KCNQ3 channels were coexpressed with M(1) muscarinic receptors. Heteromeric KCNQ2/KCNQ3 currents were modulated by the muscarinic agonist oxotremorine-M (oxo-M) in a manner having all of the characteristics of modulation of native M current in sympathetic neurons. Oxo-M also produced obvious intracellular Ca(2+) transients, observed by using indo-1 fluorescence. However, modulation of the current remained strong even when Ca(2+) signals were abolished by the combined use of strong intracellular Ca(2+) buffers, an inhibitor of IP(3) receptors, and thapsigargin to deplete Ca(2+) stores. Muscarinic modulation was not blocked by staurosporine, a broad-spectrum protein kinase inhibitor, arguing against involvement of protein kinases. The modulation was not associated with a shift in the voltage dependence of channel activation. Homomeric KCNQ2 and KCNQ3 channels also expressed well and were modulated individually by oxo-M, suggesting that the motifs for modulation are present on both channel subtypes. Homomeric KCNQ2 and KCNQ3 currents were blocked, respectively, at very low and at high concentrations of tetraethylammonium ion. Finally, when KCNQ2 subunits were overexpressed by intranuclear DNA injection in sympathetic neurons, total M current was fully modulated by the endogenous neuronal muscarinic signaling mechanism. Our data further rule out Ca(2+) as the diffusible messenger. The reconstitution of muscarinic modulation of the M current that uses cloned components should facilitate the elucidation of the muscarinic signaling mechanism.

Comparison of MRI and radiographs in the evaluation of acromial morphology.

This study compared the accuracy of magnetic resonance imaging (MRI) grading of acromions using supraspinatus outlet view radiographs. Thirty-two consecutive patients (17 men and 15 women) treated for shoulder disorders were included in the study. Average patient age was 58.5 years. All patients had both a supraspinatus outlet radiograph and an MRI of the shoulder. Each acromion was graded by three independent observers at separate intervals by radiographs and MRI and the results were compared. The incidence of the three acromial types determined by radiographs was: type I = 6%, type II = 66%, and type III = 28%. The incidence of the three acromial types determined by MRI was: type I = 6%, type II = 69%, and type III = 25%. There was essentially no difference in the incidence of acromial morphology between the two groups. Magnetic resonance imaging demonstrated the same shape as shown on the plain radiographs in 97% of the patients (95% confidence interval, 0.84-0.99). Magnetic resonance imaging is similar to supraspinatus outlet radiographs in determining acromial type. Acromial grading by MRI is a valid method of determining acromial morphology.

Assignment of muscarinic receptor subtypes mediating G-protein modulation of Ca(2+) channels by using knockout mice.

There are five known subtypes of muscarinic receptors (M(1)-M(5)). We have used knockout mice lacking the M(1), M(2), or M(4) receptors to determine which subtypes mediate modulation of voltage-gated Ca(2+) channels in mouse sympathetic neurons. Muscarinic agonists modulate N- and L-type Ca(2+) channels in these neurons through two distinct G-protein-mediated mechanisms. One pathway is fast and membrane-delimited and inhibits N- and P/Q-type channels by shifting their activation to more depolarized potentials. The other is slow and voltage-independent and uses a diffusible cytoplasmic messenger to inhibit both Ca(2+) channel types. Using patch-clamp methods on acutely dissociated sympathetic neurons, we isolated each pathway by pharmacological and kinetic means and found that each one is nearly absent in a particular knockout mouse. The fast and voltage-dependent pathway is lacking in the M(2) receptor knockout mice; the slow and voltage-independent pathway is absent from the M(1) receptor knockout mice; and neither pathway is affected in the M(4) receptor knockout mice. The knockout effects are clean and are apparently not accompanied by compensatory changes in other muscarinic receptors.

The outcome of lumbar discectomy in elite athletes.

STUDY DESIGN: An outcomes assessment of 14 elite college athletes who had undergone lumbar disc surgery was performed using the SF-36, a validated questionnaire that assesses quality of life. OBJECTIVES: To determine the outcomes and results of lumbar disc surgery in an elite group of athletes and compare the results with those in the general population and in age-matched control subjects. SUMMARY OF BACKGROUND DATA: Lumbar disc surgery is reported to be a highly successful procedure with excellent results. The outcome in elite athletes has not been assessed and compared with population norms and age-matched control subjects. METHODS: Fourteen athletes from schools in the National Collegiate Athletic Association with a mean age of 20.7, underwent lumbar discectomy for radiculopathy refractory to conservative treatment. Ten had a single-level microdiscectomy, three a two-level microdiscectomy, and one a percutaneous discectomy. Patients were evaluated at a mean follow-up of 3.1 years, underwent a detailed clinical evaluation, and filled out the SF-36 questionnaire. RESULTS: All 14 patients had improvement of pain with elimination of the radicular component, took less medication than before surgery, and returned to recreational sports. Nine patients, all with a single level microdiscectomy, returned to varsity sports. Five athletes prematurely retired from competitive sports because of continued symptoms. Three of the athletes who retired underwent two-level procedures, and one had a percutaneous discectomy. SF-36 scores for bodily pain, physical role, and social and mental health roles were significantly lower in those athletes who retired. Patient scores were also compared with those in a group of noninjured age-and sport-matched college athletes. There were no differences between injured and noninjured athletes, but both groups had scores significantly lower than normal values in an age-matched group for bodily pain, physical role, general health, and social function. CONCLUSIONS: All patients were satisfied with their surgeries, were greatly improved, and were pain free in activities of daily living. For a single-level microdiscectomy, the success rate in elite athletes is excellent, with 90% of athletes able to return to a high level of competition. Two-level disease may be associated with a less favorable outcome.

Cysts and other masses about the knee: identifying and treating common and rare lesions.

Masses about the knee are most commonly benign cysts. The diagnosis can often be made with a history and physical exam, but radiographs and MRI are sometimes required, and histologic evaluation is occasionally necessary. Popliteal (Baker's) cysts are often indicative of arthritis; treatment for the underlying pathology may reduce swelling and permit resorption. Meniscal cysts indicate an underlying tear; treatment is resection and cyst excision. Symptomatic ganglion cysts generally require surgical excision. Treatment for bursitis is conservative. The less-common synovial chondromatosis, pigmented villonodular synovitis, synovial sarcoma, and lesions of the proximal tibiofibular joint generally require referral and surgery.

Stoichiometry and arrangement of heteromeric olfactory cyclic nucleotide-gated ion channels.

Native cylic nucleotide-gated (CNG) channels are composed of alpha and beta subunits. Olfactory CNG channels were expressed from rat cDNA clones in Xenopus oocytes and studied in inside-out patches. Using tandem dimers composed of linked subunits, we investigated the stoichiometry and arrangement of the alpha and beta subunits. Dimers contained three subunit types: alphawt, betawt, and alpham. The alpham subunit lacks an amino-terminal domain that greatly influences gating, decreasing the apparent affinity of the channel for ligand by 9-fold, making it a reporter for inclusion in the tetramer. Homomeric channels from injection of alphawtalphawt dimers and from alphawt monomers were indistinguishable. Channels from injection of alphawtalpham dimers had apparent affinities 3-fold lower than alphawt homomultimers, suggesting a channel with two alphawt and two alpham subunits. Channels from coinjection of alphawtalphawt and betabeta dimers were indistinguishable from those composed of alpha and beta monomers and shared all of the characteristics of the alpha+beta phenotype of heteromeric channels. Coinjection of alphawtalpham and beta beta dimers yielded channels also of the alpha+beta phenotype but with an apparent affinity 3-fold lower, indicating the presence of alpham in the tetramer and that alpha+beta channels have adjacent alpha-subunits. To distinguish between an alpha-alpha-alpha-beta and an alpha-alpha-beta-beta arrangement, we compared apparent affinities for channels from coinjection of alphawtalphawt and betaalphawt or alphawtalphawt and betaalpham dimers. These channels were indistinguishable. To further argue against an alpha-alpha-alpha-beta arrangement, we quantitatively compared dose-response data for channels from coinjection of alphawtalpham and beta beta dimers to those from alpha and beta monomers. Taken together, our results are most consistent with an alpha-alpha-beta-beta arrangement for the heteromeric olfactory CNG channel.

Genetic and experimental evidence for cross-species infection by swine hepatitis E virus.

Prior to the recent discovery of the swine hepatitis E virus (swine HEV) in pigs from the midwestern United States, HEV was not considered endemic to this country. Since swine HEV is antigenically and genetically related to human strains of HEV, it was important to characterize this new virus further. The infectivity titer of a pool of swine HEV in pigs was determined in order to prepare a standardized reagent and to evaluate the dose response in pigs. Although the sequence of swine HEV varied extensively from those of most human strains of HEV, it was very closely related to the two strains of human HEV (US-1 and US-2) isolated in the United States. The U.S. strains which were recently recovered from two patients with clinical hepatitis E in the United States shared >/=97% amino acid identity with swine HEV in open reading frames 1 and 2. Phylogenetic analyses of different regions of the genome revealed that swine HEV and the U.S. strains grouped together and formed a distinct branch. These results suggested that swine HEV may infect humans. When we inoculated rhesus monkeys and a chimpanzee, experimental surrogates of humans, with swine HEV, the primates became infected. Furthermore, in a reciprocal experiment, specific-pathogen-free pigs were experimentally infected with the US-2 strain of human HEV that is genetically similar to swine HEV. These results provided experimental evidence for cross-species infection by the swine virus. Thus, humans appear to be at risk of infection with swine HEV or closely related viruses.