Impaired long-term potentiation in the prefrontal cortex of Huntington's disease mouse models: rescue by D1 dopamine receptor activation.

BACKGROUND: The introduction of gene testing for Huntington's disease (HD) has enabled the neuropsychiatric and cognitive profiling of human gene carriers prior to the onset of overt motor and cognitive symptoms. Such studies reveal an early decline in working memory and executive function, altered EEG and a loss of striatal dopamine receptors. Working memory is processed in the prefrontal cortex and modulated by extrinsic dopaminergic inputs. OBJECTIVE: We sought to study excitatory synaptic function and plasticity in the medial prefrontal cortex of mouse models of HD. METHODS: We have used 2 mouse models of HD, carrying 89 and 116 CAG repeats (corresponding to a preclinical and symptomatic state, respectively) and performed electrophysiological field recording in coronal slices of the medial prefrontal cortex. RESULTS: We report that short-term synaptic plasticity and long-term potentiation (LTP) are impaired and that the severity of impairment is correlated with the size of the CAG repeat. Remarkably, the deficits in LTP and short-term plasticity are reversed in the presence of a D(1) dopamine receptor agonist (SKF38393). CONCLUSION: In a previous study, we demonstrated that a deficit in long-term depression (LTD) in the perirhinal cortex could also be reversed by a dopamine agonist. These and our current data indicate that inadequate dopaminergic modulation of cortical synaptic function is an early event in HD and may provide a route for the alleviation of cognitive dysfunction.

Do GLP-1RAs and SGLT-2is reduce cardiovascular events in women with type 2 diabetes? A systematic review and meta-analysis.

AIMS: The risk of cardiovascular disease is often underestimated in women. This leads to a delay in controlling the risk factors for cardiovascular disease and even delays in prescribing medications with cardiovascular benefit. Our aim was to explore if glucagon-like peptide-1 receptor agonist (GLP-1RA) or sodium-glucose cotransporter-2 inhibitor (SGLT-2i) medications would reduce cardiovascular events in women with type 2 diabetes when atherosclerotic cardiovascular disease (ASCVD) predominates. MATERIALS AND METHODS: We searched for randomized trials comparing GLP-1RA or SGLT-2i to placebo in people with type 2 diabetes and had a primary outcome exploring major adverse cardiovascular events (MACE). Data concerning women were then extracted. A sensitivity and subgroup analyses were performed according to the class of diabetes medication. RESULTS: A total of 9 trials (GLP-1RA in 6 trials and SGLT-2i in 3) were included. Of the 84,258 participants enrolled, 30,784 (37%) participants were women. Pooled results showed a statistically significant lower incidence of MACE favouring diabetes medications (GLP-1RA or SGLT-2i) compared to placebo (RR [95%CI]=0.87 [0.80, 0.94]). On restricting the analysis to GLP-1RA then to SGLT-2i, results remained significant with GLP-1RA but not SGLT-2i. CONCLUSIONS: In women with type 2 diabetes who either have increased cardiovascular risk or established cardiovascular disease and ASCVD predominates, GLP-1RA significantly reduce the incidence of MACE while SGLT-2i result in a non-significant reduction. SGLT-2i may have comparable effect when examined in more studies. GLP-1RA and SGLT-2i should be considered without delay in women with type 2 diabetes and increased risk for cardiovascular disease.

Comparing once-weekly semaglutide to incretin-based therapies in patients with type 2 diabetes: a systematic review and meta-analysis.

AIMS: Our aim was to compare once-weekly semaglutide to incretin-based therapies - defined as either dipeptidyl peptidase-4 inhibitors (DPP-4i) or other glucagon-like peptide-1 receptor agonist (GLP-1RA) - in patients with type 2 diabetes. METHODS: We searched for randomized trials comparing once-weekly semaglutide to other incretin-based therapies in patients with type 2 diabetes. We pooled trials that compared semaglutide to other GLP-1RA together, and those comparing semaglutide to DPP-4i together. The primary outcome was the change in haemoglobin A1c over time. RESULTS: Five trials met our inclusion criteria. There was a significantly greater reduction in haemoglobin A1c favouring semaglutide when compared to other GLP-1RA or DPP-4i [MD (95% CI) = -0.38% (-0.62, -0.15) and -1.14% (-1.53, -0.75) respectively]. There was a significantly greater weight loss favouring semaglutide when compared to other GLP-1RA or DPP-4i [MD (95% CI) = -2.50 kg (-3.91, -1.09) and -3.19 kg (-3.66, -2.72) respectively]. The proportion of patients achieving glycaemic goals and goal weight loss was greater in semaglutide-treated patients when compared to either other GLP-1RA or DPP-4i. However, semaglutide-treated patients had a significantly higher incidence of gastrointestinal side effects. CONCLUSIONS: While both once-weekly semaglutide and other incretin-based therapies can reduce haemoglobin A1c, semaglutide causes a more potent haemoglobin A1c reduction and greater weight loss when compared to other incretin-based therapies. However, this potent effect of semaglutide was associated with a higher incidence of gastrointestinal side effects. Additional studies are needed to determine whether this marked reduction in both haemoglobin A1c and body weight may translate into improved cardiovascular outcomes.

Comparing SGLT-2 inhibitors to DPP-4 inhibitors as an add-on therapy to metformin in patients with type 2 diabetes: A systematic review and meta-analysis.

AIMS: Our aim was to compare Sodium-glucose co-transporter 2 inhibitors (SGLT-2i) to Dipeptidyl peptidase-4 inhibitors (DPP-4i) as add-on therapy to metformin. METHODS: We searched for randomized trials comparing SGLT-2i to DPP-4i as add-on therapy to metformin in Type 2 diabetes.We pooled trials reporting outcomes between 12 and 26 weeks together while trials reporting results ≥52 weeks were pooled together. The primary outcomes were the change in haemoglobin A1c (A1c) at ≤26 and ≥52 weeks. Sensitivity analyses were performed according to the dose of SGLT-2i and according to baseline A1c for the primary outcomes. RESULTS: Seven trials met our inclusion criteria. There was a statistically significant reduction in A1c at ≥52 weeks favouring SGLT-2i compared to DPP-4i (MD [95% CI]=-0.11% [-0.20, -0.03]) but no significant difference at ≤26 weeks (MD [95% CI]=-0.05% [-0.16, 0.05]). SGLT-2i caused significantly more weight loss compared to DPP-4i at ≤26 weeks and ≥52 weeks (MD [95% CI]=-2.31kg [-2.66, -1.96] and -2.45kg [-2.83, -2.07], respectively). SGLT-2i treated patients had a significantly more genital infection compared to DPP-4i. On restricting the analysis according to the SGLT-2i FDA-approved dose, only higher doses at ≥52 weeks showed a statistically significant reduction in A1c compared to DPP-4i. On restricting the analysis according to baseline A1c, results favoured DPP-4i if baseline A1c was<8.5%, but favoured SGLT-2i if ≥8.5%. CONCLUSION: While both SGLT-2i and DPP-4i can reduce A1c, SGLT-2i causes a more robust A1c reduction and more weight loss but with more genital infections. Higher doses of SGLT-2i showed more efficacy when compared to DPP-4i; however, this data should be interpreted cautiously given the limited number of trials.

Targeted deletion of a cyclic nucleotide-gated channel subunit (OCNC1): biochemical and morphological consequences in adult mice.

The olfactory cyclic nucleotide-gated channel subunit 1 (OCNC1) is required for signal transduction in olfactory receptor cells. To further investigate the role of this channel in the olfactory system, the biochemical and morphological consequences of targeted disruption of OCNC1 were investigated in adult mice. Null as compared to wild-type mice had smaller olfactory bulbs, suggesting compromised development of the central target of the receptor cells. Ectopic olfactory marker protein (OMP)-stained fibers localized to the external plexiform layer reflected the relative immaturity of the olfactory bulb in the null mice. The olfactory epithelium of the knock-out mouse was thinner and showed lower expression of olfactory marker protein and growth-associated protein 43, indicating decreases in both generation and maturation of receptor cells. Tyrosine hydroxylase (TH) expression in the olfactory bulb, examined as a reflection of afferent activity, was reduced in the majority of periglomerular neurons but retained in atypical or "necklace" glomeruli localized to posterior aspects of the olfactory bulb. Double label studies demonstrated that the remaining TH-immunostained neurons received their innervation from a subset of receptor cells previously shown to express a phosphodiesterase that differs from that found in most receptor cells. These data indicate that expression of OCNC1 is required for normal development of the olfactory epithelium and olfactory bulb. The robust expression of TH in some periglomerular cells in the OCNC1-null mice suggests that receptor cells innervating these glomeruli may use an alternate signal transduction pathway.

The role of calcium channel blockers in the treatment of essential hypertension.

Calcium channel blockers, originally developed for the treatment of angina and supraventricular arrhythmias, have been shown to lower elevated blood pressure effectively in hypertensive patients. Verapamil, nifedipine, and diltiazem represent prototype compounds for unique chemical classes with differing pharmacologic properties. These drugs lower elevated blood pressure with efficacy comparable with other commonly used antihypertensives. Combination therapy with other agents usually results in an additive response. Side effects are usually mild and reversible and usually are an extension of the drug's pharmacologic effects. Moreover, adverse metabolic effects on lipid, glucose, or potassium levels are not common. Because of the excellent antihypertensive effects of calcium channel blockers and their potential importance in a variety of other disease states, these agents should be routinely considered for use as a first-line antihypertensive agent in appropriately selected patients with hypertension of any severity as part of a comprehensive plan to minimize cardiovascular risk.

Hippocampal circuit dysfunction in the Tc1 mouse model of Down syndrome.

Hippocampal pathology is likely to contribute to cognitive disability in Down syndrome, yet the neural network basis of this pathology and its contributions to different facets of cognitive impairment remain unclear. Here we report dysfunctional connectivity between dentate gyrus and CA3 networks in the transchromosomic Tc1 mouse model of Down syndrome, demonstrating that ultrastructural abnormalities and impaired short-term plasticity at dentate gyrus-CA3 excitatory synapses culminate in impaired coding of new spatial information in CA3 and CA1 and disrupted behavior in vivo. These results highlight the vulnerability of dentate gyrus-CA3 networks to aberrant human chromosome 21 gene expression and delineate hippocampal circuit abnormalities likely to contribute to distinct cognitive phenotypes in Down syndrome.

Disposition of digoxin immune Fab in patients with kidney failure.

Digoxin and digoxin immune Fab, its antidote, are eliminated renally. However, the disposition of Fab in severe kidney disease is poorly described. Therefore, the disposition of Fab and its relationship to total and free digoxin were studied in five digoxin-toxic patients with end-stage renal disease (n = 4) or severe renal dysfunction (n = 1) with a mean (+/- SD) serum creatinine of 5.9 +/- 1.2 mg/dl (four patients were receiving long-term hemodialysis). Serum was drawn after a clinically neutralizing Fab dose (80 to 160 mg) every 12 to 24 hours for 204 to 327 hours. Fab concentrations were assessed by radioimmunoassay, whereas total digoxin concentrations were assessed with a modified radioimmunoassay or fluorescence polarization immunoassay. The concentration-time profile of Fab appeared to be similar to the concentration-time profile of total digoxin. The mean (+/- SD) half-lives of the alpha and beta disposition phases of Fab were 13 +/- 5 hours and 96 +/- 31 hours, respectively, which were similar to the alpha and beta parameter estimates of total digoxin (14 +/- 4 and 123 +/- 16 hours, respectively). Steady-state volume of distribution and systemic clearance of Fab were 0.29 +/- 0.11 L/kg and 0.057 +/- 0.022 ml/min/kg, respectively. Thus, in comparison to values reported in patients with normal renal function, the elimination of Fab and total digoxin are markedly delayed in patients with end-stage renal disease, which may necessitate prolonged clinical monitoring.

Pattern of olfactory bulb innervation returns after recovery from reversible peripheral deafferentation.

The olfactory epithelium (OE) is unusual in its ability to regenerate and reinnervate its target, the olfactory bulb (OB), after deafferentation. To address the question of whether olfactory receptor neuron (ORN) axons preserve their topographic organization when they reestablish synaptic contact with the OB, the authors examined the pattern of ORN axon reinnervation into the bulb of adult H-OMP-lacZ-6 transgenic mice during and after recovery from chemical deafferentation. In the H-OMP-lacZ-6 mouse strain, lacZ expression is limited to a subset of ORNs that are distributed bilaterally in the OE and project primarily to a few glomeruli in the ventromedial region of the OB. The OE was lesioned by intranasal irrigation with Triton X-100, and the distribution of 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside (X-gal)-stained cells was examined in the OE along with beta-galactosidase-immunoreactive (beta-gal-ir) axonal processes in the OB after short (1 week), intermediate (3 week), and long (6-7 weeks) recovery times. One week after the lesion, immunostaining for beta-gal and olfactory marker protein was virtually eliminated in the bulb. After 3 weeks of recovery, beta-gal-containing axons appeared to target many of the same locations innervated in bulbs of unlesioned mice. The region that received the highest density of axonal innervation in controls, however, contained only a few processes at that time. After 6-7 week recovery periods, the pattern of X-gal staining in the OE and beta-gal-ir axons in the OB closely resembled that of unlesioned mice. These results demonstrate that the topographic distribution of ORNs in the OE and the pattern of axon innervation in the OB can be reconstituted after chemical deafferentation.

Radiometric detection of the metabolic activity of Mycobacterium tuberculosis.

A radiometric test capable of detecting the metabolic rate of M. tuberculosis within 18 hr after inoculation has been developed. The technique is based on the measurement of 14CO2 produced by the bacterial metabolism of 14C-U-glycerol of 14C-U-acetate. The test is an important first step in the development of rapid radiometric techniques for clinical study of Mycobacterium tuberculosis.

The effect of tolmetin on the chronic pain and decreased functional capacity associated with degenerative joint disease.

Degenerative joint disease (DJD) is a common disorder characterized by chronic pain and limitation of activity, for which treatment with a nonsteroidal anti-inflammatory drug (NSAID) is often useful. The anti-inflammatory activity of the NSAID tolmetin sodium has been well described, being comparable in efficacy to indomethacin and effective for the relief of the acute and chronic symptoms that accompany DJD. To examine specifically the effect of tolmetin in controlling the pain and functional limitation in DJD of the spine, tolmetin was tested against placebo in a double-blind, two-segment, crossover study. Twenty-six patients (mean age, 62.5 years; range, 42-79 years) received three weeks of tolmetin 1,200 mg/d and three weeks of placebo. The results showed that tolmetin provided significantly greater relief of symptoms than placebo in virtually all measurements of joint pain and stiffness: tenderness, pain at rest, pain on motion, intensity of joint pain (P less than 0.001), and duration of morning stiffness (P = 0.002). Statistically significant improvement was noted in two of the three measures of cervical range of motion (P less than or equal to 0.01) and in all assessments of daily living activities (P = 0.001 in four parameters; P = 0.02 in a fifth parameter). Global evaluations of response to treatment by both patients and investigator also demonstrated significant effects (P less than or equal to 0.002). Significantly more placebo patients (13 of 26) than tolmetin patients (two of 26) found the medication ineffective and discontinued treatment prematurely (P = 0.01). No serious or limiting adverse reactions were seen during placebo or tolmetin therapy. The most frequently reported side effects on both therapies were gastrointestinal.(ABSTRACT TRUNCATED AT 250 WORDS)

Lack of effect of pentoxifylline on red blood cell deformability.

The proposed mechanism of action for pentoxifylline's beneficial effect in peripheral vascular disease is an improvement in red blood cell deformability. Likewise, single doses of pentoxifylline in healthy volunteers have been shown to improve whole blood filterability, which was suggested to occur as a result of augmented red blood cell deformability. To further assess this, the authors studied the effects of short-term pentoxifylline administration (400 mg three times daily for 7 days) on red blood cell deformability in ten healthy, methylxanthine-free, nonsmoking volunteers. Blood samples were obtained at baseline and after 1 week of therapy (steady-state). Samples were analyzed for red blood cell deformability by ektacytometry, which showed no significant change in deformability in any subject. Despite the improvement in whole blood filterability associated with both single-dose and short-term administration of pentoxifylline, the current study demonstrates no effect on red blood cell deformability after short-term administration in healthy volunteers.

Clinical pharmacology and therapeutics in primary care: an elective for fourth-year medical students.

A 1-month elective course in clinical pharmacology in primary care has been developed and is offered six times a year for fourth-year medical students. The major course objective is to teach the student to apply the principles of rational therapeutics in the routine practice of primary care. The faculty includes clinical pharmacists and primary care physicians from the Department of Family Medicine. Two students each month rotate through a combined didactic and experiential curriculum oriented toward the rational selection and monitoring of drugs in inpatient and outpatient settings. Students interact daily with faculty members and have ample opportunity to evaluate drug therapy regimens and assist in designing new therapeutic strategies. Students are evaluated on their performance in conferences, written consultations, and oral case challenges. Evaluations by students indicate that this elective is a valuable educational experience.

Lipid and lipoprotein responses to oral combined hormone replacement therapy in normolipemic obese women with controlled type 2 diabetes mellitus.

This study investigated the effects of oral combined hormone replacement therapy (OCHRT) on lipid concentrations and subpopulation distribution of lipoproteins in nine postmenopausal women with type 2 diabetes mellitus and moderate glycemic control. After 16 weeks of continuous daily therapy of conjugated estrogens 0.625 mg and medroxyprogesterone 2.5 mg, the mean concentration of high-density lipoprotein (HDL) cholesterol showed a statistically significant increase of 16.7%, predominantly in the HDL2 subfraction. No statistically significant changes in mean concentrations of total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, very low-density lipoprotein (VLDL) triglycerides, apolipoprotein A1, or apolipoprotein B were evident. Likewise, no changes were found in the average diameter of VLDL, LDL, or HDL particles; triglyceride concentrations of VLDL subfractions; cholesterol concentrations of LDL subfractions; or chemical composition of plasma LDL. These findings lend further support to the use of OCHRT in postmenopausal women with diabetes to decrease their risk for coronary artery disease.

The antihypertensive response to lisinopril: the effect of age in a predominantly black population.

After a 2-4 week no-treatment period, 24 patients (12 young, age 29-45 yr.; 12 elderly, age 65-81 yr.; 20 black, 4 white) with an untreated sitting diastolic blood pressure between 91-120 mm Hg received the nonsulfhydryl angiotensin converting enzyme inhibitor, lisinopril for three weeks in a singleblind, parallel group comparison. Patients who did not achieve goal blood pressure with the initial low-dose (10 mg/day) were treated with a high-dose regimen (40 mg/day) for three weeks. In those who remained incompletely responsive, hydrochlorothiazide 25 mg/day was added for four weeks in an attempt to normalize blood pressure (less than or equal to 90 mm Hg). Low-dose lisinopril monotherapy produced comparable reductions in the mean systolic and diastolic blood pressures (approximately -15/-8 mm Hg in both younger and older patients). Increasing the dose produced a slightly greater fall in mean blood pressures which normalized the blood pressure in five of six elderly patients unresponsive to the lower dose; addition of hydrochlorothiazide normalized three of the five remaining subjects from both groups who were unresponsive to high dose lisinopril. Lisinopril administration resulted in a rise in plasma renin activity and a fall in plasma aldosterone concentrations which were similar in both groups and which returned over time toward the baseline. The drug was well tolerated, producing one episode of symptomatic hypotension following the addition of hydrochlorothiazide to lisinopril monotherapy. Lisinopril alone or in combination with hydrochlorothiazide produces favorable antihypertensive effects in both younger and older predominantly black, low-renin patients with essential hypertension.

Migrating luteinizing hormone-releasing hormone (LHRH) neurons and processes are associated with a substrate that expresses S100.

Luteinizing hormone-releasing hormone (LHRH) containing neurons arise in the region of the medial olfactory placode and migrate into the developing olfactory bulbs and basal forebrain along branches of the terminal and vomeronasal nerves. The neurons ultimately come to reside in olfactory and septo-preoptic areas and project extensively to several brain regions, including the preoptic area and median eminence. The present study examined the expression of a glial-associated guidance molecule, S100, as a possible substrate for this migration. Monodelphis domestica (the Brazilian grey, short-tailed opossum) was studied since this species gives birth to very immature, young, allowing access to early periods of mammalian forebrain development. Immunoreactivity for both S100 and LHRH-containing neurons and fibers were observed to be closely associated along the entire LHRH migratory route from the vomeronasal organ to the septo-preoptic areas as early as the day of birth (PO). By P10, S100-immunoreactivity was also seen in areas containing LHRH-immunoreactive fibers such as the preoptic area and median eminence. We suggest that S100, a protein with neurotrophic properties in vitro, acts as a guidance molecule for migrating LHRH-immunoreactive neurons and elongating processes.

Failure of prostatitis treatment secondary to probable ciprofloxacin-sucralfate drug interaction.

Metal cations such as aluminum, magnesium, ferrous sulfate, and zinc are thought to form chelation complexes with fluoroquinolone antibiotics and prevent the drugs from being absorbed. Sucralfate, which has a high aluminum content, reduces the bioavailability of ciprofloxacin to approximately 4%. The concomitant administration of ciprofloxacin and sucralfate resulted in treatment failure for a patient with prostatitis and a subsequent 5-day hospitalization. Fluoroquinolone antibiotics should be administered at least 2 hours before agents containing metal cations to allow for their absorption. In addition, sucralfate should not be administered less than 6 hours before fluoroquinolone antibiotic administration.

Influence of pentoxifylline on steady-state theophylline serum concentrations from sustained-release formulations.

This clinical study assessed the influence of pentoxifylline and its metabolites on steady-state serum theophylline concentrations. Nine healthy volunteers took sustained-release formulations of pentoxifylline, theophylline, and a combination of both agents each for 7 days at standard therapeutic doses in a randomized order. Serum theophylline concentrations were analyzed using fluorescence-polarization immunoassay (TDx) technique. During the pentoxifylline treatment phase, serum theophylline concentrations were undetectable, demonstrating the lack of assay interference from pentoxifylline and its metabolites. Mean trough steady-state serum theophylline concentrations were 30% higher (p less than 0.05) during the combination treatment phase compared to theophylline administration alone, and varied considerably. Although side effects were more frequent during the combination phase, differences in the number of adverse reactions did not achieve statistical significance. This study demonstrates an interaction between theophylline and pentoxifylline, and indicates that close monitoring of serum theophylline concentrations during combination therapy is warranted.

Exploring psychiatric prescribing practices: the relationship between the role of the provider and the appropriateness of prescribing.

The prescribing habits of psychiatrists and neurologists in a large, urban Veterans Administration medical center were surveyed. It was determined that these physicians prescribed a large amount of nonpsychotropic medication, and the rationale for this practice was explored and is presented. Patient expectations in this population derived from certain established sociocultural biases toward the medical profession appeared to significantly influence prescribing practices. Such prescribing behavior suggests that the psychiatrist in this setting is often required to assume the role of primary care provider as part of a larger patient therapist relationship.

Screening for diabetic retinopathy in rural areas: the potential of telemedicine.

Diabetic retinopathy is a common cause of blindness, and screening can identify the disease at an earlier, more treatable stage. However, rural individuals with diabetes may have limited access to needed eye care. The objective of this project was to demonstrate the feasibility of a diabetic retinopathy screening program using a state-of-the-art nonmydriatic digital fundus imaging system. The study involved a series of patients screened in primary care and public health locations throughout seven predominantly rural counties in eastern North Carolina. Images of each fundus were obtained and sent to a retinal specialist. The retinal specialist reviewed each image, recorded image quality, diagnosed eye disease and made recommendations for subsequent care. Of 193 volunteers with a history of diabetes mellitus, 96.3 percent reported that they were very comfortable or comfortable with the camera. Eighty-five percent of images were rated as good or fair by the retinal specialist. The retinal specialist also reported being very certain or certain of the diagnosis in 84 percent of cases. Image quality correlated highly with the certainty of diagnosis (Spearman's rank order correlation coefficient = 0.79; P < 0.001). The average time since the previous examination by an eye care specialist for diabetic subjects was two years. Approximately 62 percent of diabetic patients had diagnosable eye conditions, the most common of which was diabetic retinopathy (40.9 percent). In this convenience sample, African Americans, despite similar age and disease duration, were more likely to have retinopathy. Digital imaging is a feasible screening modality in rural areas, may improve access to eye care, and may improve compliance with care guidelines for individuals with diabetes mellitus.