Dopamine D1 receptor subtype mediates acute stress-induced dendritic growth in excitatory neurons of the medial prefrontal cortex and contributes to suppression of stress susceptibility in mice.

Dopamine in prefrontal cortices is implicated in cognitive and emotional functions, and the dysfunction of prefrontal dopamine has been associated with cognitive and emotional deficits in mental illnesses. These findings have led to clinical trials of dopamine-targeting drugs and brain imaging of dopamine receptors in patients with mental illnesses. Rodent studies have suggested that dopaminergic pathway projecting to the medial prefrontal cortex (mPFC) suppresses stress susceptibility. Although various types of mPFC neurons express several dopamine receptor subtypes, previous studies neither isolated a role of dopamine receptor subtype nor identified the site of its action in mPFC. Using social defeat stress (SDS) in mice, here we identified a role of dopamine D1 receptor subtype in mPFC excitatory neurons in suppressing stress susceptibility. Repeated social defeat stress (R-SDS) reduces the expression of D1 receptor subtype in mPFC of mice susceptible to R-SDS. Knockdown of D1 receptor subtype in whole neuronal populations or excitatory neurons in mPFC facilitates the induction of social avoidance by SDS. Single social defeat stress (S-SDS) induces D1 receptor-mediated extracellular signal-regulated kinase phosphorylation and c-Fos expression in mPFC neurons. Whereas R-SDS reduces dendritic lengths of mPFC layer II/III pyramidal neurons, S-SDS increases arborization and spines of apical dendrites of these neurons in a D1 receptor-dependent manner. Collectively, our findings show that D1 receptor subtype and related signaling in mPFC excitatory neurons mediate acute stress-induced dendritic growth of these neurons and contribute to suppression of stress susceptibility. Therefore, we propose that D1 receptor-mediated dendritic growth in mPFC excitatory neurons suppresses stress susceptibility.

Metachronous Contralateral Breast Cancer in Ahmadu Bello University Teaching Hospital, Zaria, Northwestern Nigeria.

Background: Breast cancer is the most frequent cancer of women. Metachronous contralateral breast cancer (MCBC) is a cancer in the contralateral breast after 6 months of the initial diagnosis of the first breast cancer. It is an important public health issue because of an increased incidence of a primary breast cancer and improved survival. There is a paucity of data in the Northwestern region of the country. The study was to document the incidence, the method of detection, clinicopathological features, and the treatment of MCBC in our hospital. Patients and Methods: It was a 7-year prospective study from January 2011 to December 2017. Patients who had treatment for nonmetastatic breast cancer, American Joint Committee on Cancer (AJCC) Stages 1-111, were followed up. Those that developed MCBC were studied. Age, the method of detection, stage at presentation, pathological types, hormone receptor status, and treatment were documented. Data obtained were analysed using SPSS version 21.0. Results were presented as simple percentages and charts. Results: Of 1285 women with nonmetastatic breast cancer, 47 had MCBC (incidence of 3.7%); 30 (63.8%) were aged 21-50 years; 23 (48.9%) detected by self-breast examination; 13 (27.7%) by clinical breast examination; seven (14.9%) by mammography; and four (8.5%) by breast ultrasound scan. Fourteen (29.8%) were AJCC stage I; 23 (48.9%), stage II; seven (14.9%), stage III; and three (6.4%), stage IV. Thirty-nine (83%) were invasive ductal carcinoma; 22 (50.0%) were estrogen receptor/progesterone receptor (ER/PR) positive, human epidermal receptor (HER)-2 neu negative; nine were (20.5%) ER/PR and HER-2 neu positive; six (13.6%) were ER/PR negative, HER-2 neu positive, whereas seven (15.9%) were triple negative. Forty-three (91.5%) had modified radical mastectomy and 19 (40.4%) had cytotoxics. Conclusion: With an average of six cases in a year, MCBC is common in our hospital. Majority (63.8%) were young. The commonest method of detection was by self-breast examination. Majority (78.3%) presented at an early stage. Most (91.5%) still had modified radical mastectomy.

Bacteremic infection in hemodialysis.

This is a retrospective study of 133 episodes of bacteremic infection in 112 hemodialysis patients. The frequency of bacteremic infection was 9.5% in patients with chronic renal failure and 10.9% in patients with acute renal failure. In patients with acute renal failure, pneumonia and intra-abdominal abscess were the most frequent sources of septicemia. Sepsis was usually due to Gram-negative organisms and mortality was high. In patients with chronic renal failure, infection of the shunt or fistula was the most common cause, was frequently due to Staphylococcus organism, and had a more favorable survival rate. Gram-negative septicemia from a nonaccess source in patients with chronic renal failure was associated with a higher mortality. Bacterial endocarditis and septic pulmonary emboli occurred in 3.6% of septic episodes and 0.35% of patients at risk and had very low mortality. A low threshold for obtaining blood cultures and early antibiotic treatment are believed to be important in the treatment of bacteremic infections in patients undergoing long-term hemodialysis.

Vestibular toxicity of gentamicin. Incidence in patients receiving long-term hemodialysis therapy.

Twenty-three patients on long-term hemodialysis regimens who received gentamicin sulfate were reviewed retrospectively to assess the incidence of ototoxicity and to identify potential risk factors. Dosage of gentamicin sulfate was 1.0 to 1.5 mg/kg intravenously three times weekly. Serum gentamicin levels were monitored in 21 cases. Seven patients developed signs and symptoms of vestibular dysfunction. Statistically significant differences were found between the ototoxic and nonototoxic groups with respect to age (P less than .001), total dose (milligrams per kilogram) (P less than .001), and duration of therapy (P less than .001). The total dose per kilogram of body weight contributed most heavily to ototoxicity, and regression analysis suggests that the critical cumulative dose is about 17.5 mg/kg. The two groups did not differ with respect to mean peak and valley serum levels. We conclude that this population is at high risk of developing gentamicin-related vestibular dysfunction specifically when the cumulative dose exceeds 17.5 mg/kg.

Adriamycin-induced alterations of the action potential in rat papillary muscle.

The present study investigates the effects of adriamycin on the electrophysiological properties of the myocardium as monitored by intracellular recordings of the cardiac action potential. ADR was administered to rats at a dose of 20 mg . kg-1 given as a single intravenous injection or in four daily doses of 5 mg . kg-1 each. Twenty-four hours following the last injection, papillary muscles were removed and intracellular recordings of the action potential were sampled from the tissue. In another set of experiments, papillary muscles were removed from non-injected, control animals and superfused in vitro with adriamycin at a concentration of 200 mumol . litre-1. Several parameters of the action potential were measured and compared with control values in both in vivo and in vitro experiments. In all studies, the major effect of adriamycin on the cardiac action potential was shown to be a prolongation of the duration at 20%, 50% and 98% repolarisation. Adriamycin did not appear to exert its effect by depression of cell metabolism, as superfusion with NaCN or dinitrophenol reduced the action potential duration. The upstroke velocity, which is proportional to the sodium conductance, was unaltered by ADR; it appears that ADR alters conductance of calcium and/or potassium across the myocardial membrane by an as yet unknown mechanism.

Cellular localization of lipocalin-type prostaglandin D synthase (beta-trace) in the central nervous system of the adult rat.

We applied high-resolution laser-scanning microscopy, electron microscopy, and non-radioactive in situ hybridization histochemistry to determine the cellular and intracellular localization of lipocalin-type prostaglandin D synthase, the major brain-derived protein component of cerebrospinal fluid, and its mRNA in leptomeninges, choroid plexus, and parenchyma of the adult rat brain. Both immunoreactivity and mRNA for prostaglandin D synthase were located in arachnoid barrier cells, arachnoid trabecular cells, and arachnoid pia mater cells. Furthermore, meningeal macrophages and perivascular microglial cells, identified by use of ED2 antibody, were immunopositive for prostaglandin D synthase. In the arachnoid trabecular cells, the immunoreactivity for prostaglandin D synthase was located in the nuclear envelope, Golgi apparatus, and secretory vesicles, indicating the active production and secretion of prostaglandin D synthase. In the meningeal macrophages, prostaglandin D synthase was not found around the nucleus but in lysosomes in the cytoplasm, pointing to an uptake of the protein from the cerebrospinal fluid. Furthermore, the existence of meningeal cyclooxygenase (COX) -1 and COX-2 was investigated by Western blot, Northern blot, and reverse transcriptase-polymerase chain reaction (RT-PCR), and the colocalization of COX-2 and prostaglandin D synthase was demonstrated in virtually all cells of the leptomeninges, choroid plexus epithelial cells, and perivascular microglial cells, suggesting that these cells synthesize prostaglandin D(2) actively. Alternatively, oligodendrocytes showed prostaglandin D synthase immunoreactivity without detectable COX-2. The localization of lipocalin-type prostaglandin D synthase in meningeal cells and its colocalization with COX-2 provide evidence for its function as a prostaglandin D(2)-producing enzyme.

Evaluation of age, gender, heart rate and blood pressure changes and exercise conditioning on Doppler measured aortic blood flow acceleration and velocity during upright treadmill testing.

To evaluate the effect of upright exercise on aortic peak flow acceleration and velocity, 60 normal subjects between 15 and 74 years of age were evaluated by continuous wave Doppler during treadmill stress testing using the Bruce protocol. Subjects were divided into 3 age groups, each with 20 subjects: group 1, 21 +/- 4 years of age (mean +/- standard deviation), group 2, 36 +/- 5 years and group 3, 58 +/- 7 years. Periodic measurements of heart rate, blood pressure and Doppler blood flow velocity and acceleration were made before, during and after exercise. Continuous wave Doppler measurements were recorded from the suprasternal notch. The relation between Doppler aortic measurements and age, gender, normal heart rate and blood pressure responses during exercise, and exercise preconditioning, was evaluated. Age alone was significantly related (inversely) to immediate postexercise Doppler aortic peak blood flow peak acceleration (group 1, 55 +/- 15, group 2, 46 +/- 11 and group 3, 36 +/- 9 m/s2, p less than 0.05) and peak velocity (1.1 +/- 0.2, 1.0 +/- 0.2 and 0.8 +/- 0.2 m/s, respectively, p less than 0.01). Gender, heart rate and blood pressure changes during exercise, as well as preconditioning, had no significant effect on these flow characteristics. Consequently, the effects of normal aging must be considered when using Doppler measurements of peak aortic acceleration and velocity in the evaluation of left ventricular function, e.g., to detect or exclude the presence of coronary artery disease.

Failure of ambulatory electrocardiographic monitoring to predict results of programmed electrical stimulation. Studies in patients with clinical ventricular tachyarrhythmias.

To test for an association between the results of ambulatory electrocardiographic monitoring (AEM) and programmed electrical stimulation (PES), or whether other factors better predict the results of PES, 57 patients (36 male and 21 female patients) presenting with either ventricular fibrillation (49 percent; 28/57) or sustained ventricular tachycardia (51 percent; 29/57) were studied. Each patient underwent AEM and PES using up to three ventricular extrastimuli. Sixty-three percent (36/57) had coronary disease; and of these, ventricular tachycardia was present during AEM in 64 percent (23/36) and induced by PES in 78 percent (28/36). With the addition of patients with other cardiac diagnoses, the results were 58 percent (33/57) and 60 percent (34/57), respectively. No AEM variable was positively associated with inducible ventricular tachycardia, including frequency of ventricular premature depolarizations, multiformity, couplets, or ventricular tachycardia. Clinical variables positively associated with inducible ventricular tachycardia were coronary disease, previous myocardial infarction, left ventricular dysfunction, male sex, and a history of recurrent arrhythmia. Therefore, clinical characteristics are more useful for predicting the results of PES than information derived from AEM.

Variation in apparent serum digitalis-like factor levels with different digoxin antibodies. The "immunochemical fingerprint".

Increased levels of a circulating digoxin-like factor (DLF) occur in a number of physiologic states in which sodium homeostasis is altered, and may contribute to the pathogenesis of hypertension. We exploited the different affinities for DLF of seven antisera directed at digoxin to develop an immunochemical profile, and then employed this index to address two questions: does the same DLF species exist in several conditions associated with increased DLF levels, including pregnancy, renal failure, hepatic failure, and neonatal cord blood? Will this approach prove useful in assessing candidates proposed to be DLF? An identical profile was identified in serum from pregnant women and patients with renal or hepatic failure, and a highly significant correlation existed between DLF levels measured with antisera of high and intermediate affinity in 42 subjects with increased levels (r = 0.93; P less than .001). In patients with renal failure, when endogenous DLF levels were too low to assess the profile, concentration of the serum resulted in measurable DLF levels that had an identical profile. The profile was somewhat altered in umbilical cord blood, perhaps reflecting an influence of increased steroid hormone levels. Among agents suggested as candidates for DLF, neither lysophosphatidylcholine nor ouabain showed a profile resembling DLF. Progesterone, 17-OH-progesterone, and bufalin, on the other hand, did show substantial similarity, perhaps providing a clue to the structure of DLF. The normal plasma levels of progesterone and 17-OH-progesterone are 100- to 1000-fold too low to be candidates for DLF and bufalin was sufficiently dissimilar not to be a candidate. DLF in at least three different patient populations probably represents identical chemical species.(ABSTRACT TRUNCATED AT 250 WORDS)

Reversal of sodium pump inhibitor induced vascular smooth muscle contraction with digibind. Stoichiometry and its implications.

The possibility that a circulating sodium pump inhibitor contributes to the pathogenesis of volume-dependent hypertension via an action on vascular smooth muscle (VSM) is supported by multiple lines of investigation, but remains controversial. We had two goals in this study. The first was to compare the pattern of contractile response of rabbit aorta induced by two candidates, ouabain and a labile sodium pump inhibitor that we have identified in the peritoneal dialysate of volume-expanded hypertensive patients with chronic renal failure. Our second goal was to examine the ability of Digibind, a Fab fragment of antisera directed against digoxin, to reverse VSM contraction induced by both agents. Ouabain induced a concentration-dependent contraction, which was delayed in onset, was gradual, and reached a stable plateau after many hours. The labile sodium pump inhibitor induced a qualitatively similar series of responses. Digibind rapidly reversed the contractile responses to both sodium pump inhibitors, with a rate of relaxation that matched that induced by physical removal of the pump inhibitor from the bath. For ouabain, the Digibind:ouabain stoichiometry was highly predictable. When Digibind was present in a molar concentration equivalent to that of ouabain, or less, it had no effect. When the Digibind concentration was twice that of ouabain, complete relaxation occurred. Although the concentration:VSM response relationship for ouabain was steep, the concentration:effect interaction with Digibind was even more steep. The molar concentration of Digibind required to reverse the effects of the labile endogenous inhibitor from peritoneal dialysate was consistently lower than that for ouabain, which is compatible with either greater potency of the labile factor in VSM or greater affinity for Digibind. These findings are compatible with a role for one or more endogenous sodium pump inhibitors as the determinant of vascular smooth muscle tone in the volume-sensitive hypertension of renal disease.

Species-specific expression of microsomal prostaglandin E synthase-1 and cyclooxygenases in male monkey reproductive organs.

We investigated the tissue distribution and cellular localization of microsomal PGE synthase-1 (mPGES-1) and cyclooxygenase (COX)-1 and -2 in male monkey reproductive organs. Western blotting revealed that monkey mPGES-1 was expressed most intensely in the seminal vesicles, moderately in the testis, and weakly in the epididymis and vas deferens. The tissue distribution profile was quite different from those profiles for rats, rabbits, and pigs, e.g., rat mPGES-1 was the most abundant in the vas deferens, and the rabbit and pig enzymes, in the testis. Immunohistochemical staining with mouse monoclonal anti-human mPGES-1 antibody revealed that monkey mPGES-1 was localized in spermatogonia, Sertoli cells, and primary spermatocytes of testis and in epithelial cells of the epididymis, vas deferens, and seminal vesicles. In monkeys, COX-1 was localized in epithelial cells of the epididymis and vas deferens, whereas COX-2 was dominantly found in epithelial cells of the seminal vesicles.

Comparison of the inflammatory response to particulate polymethylmethacrylate debris with and without barium sulfate.

Particulate polymethylmethacrylate debris has been implicated in the inflammatory response observed surrounding loosened cemented implants. The rat subcutaneous pouch model and the Howie implant model (used to study bone resorption) were used to quantify the response to mechanically produced endotoxin-free polymethylmethacrylate debris with and without 10% (wt/vol) BaSO4. In the rat subcutaneous pouch model, the inflammatory response to polymethylmethacrylate particles containing BaSO4 was greater than the response to plain polymethylmethacrylate particles of similar size. Increased inflammation was measured by leukocyte counts and levels of prostaglandin E2, tumor necrosis factor, and neutral metalloprotease. In addition, particulate polymethylmethacrylate with BaSO4 caused significantly greater bone resorption in the Howie model than did particulate plain polymethylmethacrylate. In in vitro studies, particulate polymethylmethacrylate with BaSO4 stimulated more prostaglandin E2, neutral metalloprotease, and tumor necrosis factor from human monocytes in culture and stimulated greater proliferation of synovial cells than did particulate plain polymethylmethacrylate. The presence of BaSO4 appears to significantly intensify the inflammatory response to polymethylmethacrylate debris.

Vascular access for dialysis. Technics and results with newer methods.

Over a five year period, 114 patients had one or more secondary operations for access to the circulation for hemodialysis, these being a Thomas femoral shunt, saphenous vein graft, or Sparks mandril graft. The patient group was different from the general dialysis population, containing more females, more patients with diabetes, and more patients with collagen-vascular disease. Comparing duration of utility by the life table method for each technic, the femoral shunt lasted longest but with a high incidence of septic complications, the mandril graft was intermediate, and the saphenous vein graft least durable in use. The mandril is considered a tentative first choice for secondary access when the required maturation time is available.

Imaging of the foot and ankle in the injured athlete.

Currently the availability of magnetic resonance imaging has replaced much of the arthrotomography and CT scanning. The increased soft tissue contrast provided by MRI allows its use in assessing tendinous, ligamentous, cartilaginous, and in particular subtle bone marrow changes, which before its inception were never directly imaged. This article covers some of these dramatic changes and will provide the sports medicine clinician an update on current imaging techniques available to them with regard to foot and ankle injuries. Imaging of the foot and ankle has undergone a dramatic change over the last decade. The sports medicine clinician's understanding of these changes as well as the new imaging modalities available to them are of paramount importance in treating today's athlete. Modalities available in the 1970s and 1980s were usually limited to plain radiographs to be followed by bone scanning, arthrotomography, or CT scanning.

Effect of a chondral-labral defect on glenoid concavity and glenohumeral stability. A cadaveric model.

One of the primary stabilizing mechanisms of the glenohumeral joint is concavity-compression, the maintenance of the humeral head in the concave glenoid fossa by the compressive force generated by the surrounding muscles. This mechanism is active in all glenohumeral positions but it is particularly important in the functional mid-range, in which the capsule and ligaments are slack. The effectiveness of concavity-compression in the stabilization of a joint can be characterized in terms of the ratio between the maximum dislocating force that can be stabilized in a given direction and the load compressing the head into the glenoid (the stability ratio). Glenoid concavity can be described by the lateral humeral displacement during translation across the glenoid. The purpose of the present investigation was to characterize the concavity and stability ratios of normal cadaveric glenoids, to measure the effect of an anteroinferior chondral-labral defect on these parameters, and to measure the effectiveness of a simulated operative reconstruction on the restoration of glenoid concavity and the stability ratio. The chondral-labral defect created in this study reduced the height of the glenoid by approximately 80 per cent and the stability ratio by approximately 65 per cent for translation in the direction of the defect. Reconstruction of the anteroinferior aspect of the glenoid concavity with use of an autogenous biceps-tendon graft restored normal values for these variables.

MRI findings of concurrent acute DVT and dissecting popliteal cyst.

A case of concurrent popliteal vein thrombosis and a dissecting popliteal cyst noted on the same MRI exam is described. Pseudothrombophlebitis is a well known entity in which a ruptured or dissecting popliteal cyst clinically mimics thrombophlebitis; the current case can be considered "pseudo-pseudo thrombophlebitis." This case demonstrates the importance of routine review of the venous structures of the posterior fossa for all MRI exams of the knee.

Family therapy in general practice: views of referrers and clients.

Family therapy is being used in a variety of settings, including general practice. To assess the views as to the effectiveness and acceptability of a family therapy clinic in a north London surgery, questionnaires were given to general practitioners referring patients, and to clients. Replies were received from seven doctors and 20 clients, representing 11 families. There was a high level of satisfaction among general practitioners referring patients. The clinic proved to be highly acceptable for clients, with 90% agreeing that it was easier to attend a clinic at the practice than at a hospital; and only one patient thought that knowing the general practitioner worked in the practice made it harder to talk openly. Eighty per cent of patients felt the problem had improved at the time of follow up. Where the problem had not improved, 60% felt that they were dealing with it better. Almost all of the patients felt that the family therapy clinic should become a permanent part of local services. The family therapy clinic in general practice has been shown to be effective and popular with users of the service.

Elbow valgus stress radiography in an uninjured population.

Valgus instability of the elbow joint is a clinical diagnosis. However, many authors describe valgus stress radiographs as an aid in making this diagnosis. We studied valgus stress radiographs of 20 men (40 elbows) and 20 women (40 elbows), none with a history of elbow trauma or instability. The medial ulnohumeral distance was measured with no stress, valgus stress by gravity, and an applied valgus stress of 25 N (approximately 5 pounds). Measurements were made with the elbow positioned in extension and in 30 degrees of flexion. The increase in medial ulnohumeral gapping with either gravity or 5 pounds of stress was statistically significant at both extension and 30 degrees of flexion compared with the unstressed condition. The difference in ulnohumeral gapping between gravity stress and 5 pounds of valgus stress in extension and in 30 degrees of flexion was also significant. We found no differences with regard to hand dominance or sex. We conclude that uninjured elbows have significant medial ulnohumeral gapping on valgus stress radiography. Although this is an important tool in diagnosing valgus instability of the elbow, it may yield a false-positive assessment of valgus instability. Valgus stress radiographs comparing contralateral elbows may reduce the false-positive rate since there appears to be no significant difference in medial ulnohumeral gapping between the two elbows.

Complications of open anterior stabilization of the shoulder.

Complications of surgery for glenohumeral instability are relatively uncommon. When they occur, salvaging failures and obtaining a stable joint can be awesome challenges. Accurate recognition of the cause of the instability and application of the appropriate surgical technique are critical. Deficiencies of the glenoid concavity, the anterior capsule, or the subscapularis may be present and require correction. Overtightening a shoulder and eliminating its normal laxity should be avoided. Loose or malpositioned hardware about the glenohumeral joint must be recognized as soon as possible and removed. The goal of treatment is to correct the deficient stabilizing mechanisms without altering normal glenohumeral function.

Cost containment through therapeutic substitution of aminoglycosides.

A therapeutic substitution policy (TSP) for tobramycin and gentamicin sulfate was implemented at the University of Texas Medical Branch (UTMB). The policy was designed by various physician-chaired hospital committees and clinical departments that collaborated with the pharmacy service. The goal was to encourage the medical house staff to use the most economical yet safe and effective aminoglycoside, without limiting the medical team's prerogative to select among alternatives within this antibiotic group. Cost data from the first 6 months of aminoglycoside use under the new policy projected an annual savings of $139,071 in drug expenditures and $242,472 in patient charges. Following the implementation of the TSP, a concurrent drug utilization review (DUR) was performed in 50 consecutive inpatients prescribed amikacin, tobramycin, or gentamicin sulfate. The objectives were to identify those aspects of prescribing and monitoring of aminoglycosides by house staff that could be improved by specific policy and/or education, and to evaluate those specific cases in which attending physician's approval allowed house staff to prescribe an aminoglycoside other than designated in the TSP. The audit revealed that house staff were compliant with 72% of the DUR criteria; however, at least one instance (mean of 5.04 +/- 2.21) of noncompliance occurred during the treatment of each patient. The most frequently encountered deficiencies were failure to monitor for ototoxicity, incorrect orders for at least one set of serum aminoglycoside concentrations, and improper dosage adjustments for those patients with renal insufficiency. In three cases, the attending physician approved house staff use of tobramycin instead of gentamicin sulfate for reasons of organism resistance, pre-existing renal impairment, and long-term treatment of osteomyelitis.