Pathophysiology and management of Akathisia 70 years after the introduction of the chlorpromazine, the first antipsychotic.

OBJECTIVE: Akathisia is among the most troubling effects of psychiatric drugs as it is associated with significant distress on behalf of the patients, and it limits treatment adherence. Though it most commonly presents during treatment with antipsychotic drugs which block dopamine D2 receptors, Akathisia has also been reported during treatment with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), stimulants, mirtazapine, tetrabenazine and other drugs. MATERIALS AND METHODS: This article was designed as a narrative review on akathisia with a focus on its clinical presentation, pathophysiology and management. A PubMed search for akathisia was conducted which returned 8481 articles. RESULTS: Akathisia is experienced as severe restlessness commonly accompanied by dysphoria and purposeless movement which relieves subjective tension. It has been attributed to an imbalance between dopaminergic and noradrenergic neurotransmission in the basal ganglia. Acute akathisia commonly resolves upon treatment discontinuation but tardive and chronic akathisia may persist after the causative agent is withdrawn and prove resistant to pharmacological treatment. Even drugs which induce no other extrapyramidal side effects (such as clozapine, quetiapine, aripiprazole and cariprazine) may induce akathisia. A high index of suspicion should be maintained in patients with motor disabilities, drug-induced parkinsonism and those under mechanical restraint. Propranolol and low-dose mirtazapine are the most thoroughly studied pharmacological interventions for akathisia, though benzodiazepines, voltage-gated calcium channel blockers (gabapentin, pregabalin) and opioids may be effective. CONCLUSIONS: Pharmacological management may pose a challenge in chronic akathisia. Rotation between different pharmacological management strategies may be optimal in resistant cases. Discontinuation of the causative drug and use of b-blockers, mirtazapine, benzodiazepines or gabapentinoids for symptomatic relief is the basis of management.

Converging dopaminergic neurotoxicity mechanisms of antipsychotics, methamphetamine and levodopa.

OBJECTIVE: Drugs affecting dopaminergic neurotransmission may exert toxic and beneficial effects that persist after discontinuation by modulating gene expression in key brain regions. Drug addiction, cravings and the tardive symptoms associated with chronic exposure to antipsychotics are among the most common processes attributed to long-term dopaminergic neurotoxicity. The purpose of this review was to investigate the mechanisms of dopaminergic neurotoxicity induced by neuroleptic drugs, dopamine agonists, levodopa, stimulants and known dopaminergic neurotoxins MATERIALS AND METHODS: A PubMed search for each of the dopaminergic compounds in question was carried out. The heterogenous nature of the relevant preclinical studies precluded a systematic review, so a narrative review was carried out. RESULTS: The dopaminergic neurotoxins 6-oxidopamine and 1-methyl-4-phenyl-tetrahydropyridine (MPTP) promote oxidative stress and inhibit mitochondrial function, while their affinity for the dopamine transporter ensures they are attain toxic intracellular concentrations exclusively in dopaminergic neurons. Stimulants which inhibit the vesicular monoamine transporter such as amphetamine and its derivatives promote oxidative stress by greatly increasing intracellular dopamine concentrations and enabling dopamine autooxidation. Antipsychotics increase dopamine release and turnover by blocking autoinhibitory D2 receptors and lead to upregulation of post-synaptic D2 receptors. Dopamine agonists may slow the progression of Parkinson's disease by reducing dopamine turnover, but downregulation of D2 receptors may underlie their behavioural toxicity. CONCLUSIONS: Though the mechanisms have not been completely elucidated yet, it seems drugs which affect dopaminergic neurotransmission may exert long-term effects which reverse slowly upon discontinuation, if at all. Until the nature of these changes is clear it would be best to utilize drugs which affect dopaminergic neurotransmission cautiously especially if prolonged treatment is required.

Electronic decay of core-excited HCl molecules probed by THz streaking.

The ultrafast electronic decay of HCl molecules in the time domain after resonant core excitation was measured. Here, a Cl-2p core electron was promoted to the antibonding σ* orbital initiating molecular dissociation, and simultaneously, the electronic excitation relaxes via an Auger decay. For HCl, both processes compete on similar ultrashort femtosecond time scales. In order to measure the lifetime of the core hole excitation, we collinearly superimposed 40 fs soft x-ray pulses with intense terahertz (THz) radiation from the free-electron laser in Hamburg (FLASH). Electrons emitted from the molecules are accelerated (streaked) by the THz electric field where the resulting momentum change depends on the field's phase at the instant of ionization. Evaluation of a time-shift between the delay-dependent streaking spectra of photo- and Auger electrons yields a decay constant of (11 ± 2) fs for LMM Auger electrons. For further validation, the method was also applied to the MNN Auger decay of krypton. Reproduction of the value already published in the literature confirms that a temporal resolution much below the duration of the exciting x-ray pulses can be reached.

[What rheumatologists can learn from ophthalmologists]. / Was der Rheumatologe vom Augenarzt lernen kann.

Intraocular inflammation with the imprecise and broad umbrella term "uveitis" is a diagnostic and therapeutic challenge in ophthalmology. Uveitis is one of the most common causes of blindness worldwide and due to the associated costs is comparable to diabetic retinopathy. Patients can be affected by uveitis at any age. Any part of the eye may be affected. The symptoms range from complete absence of symptoms, through all types of vision deterioration up to a red and even very painful eye. Uveitis can be strictly unilateral (also alternating from the left to the right eye) or bilateral with a relapsing or chronic course. The transitions are smooth and the differential diagnoses are very broad. In addition to infectious forms and ocular syndromes restricted to the eye, it also includes those with extraocular systemic diseases, such as ankylosing spondylitis or sarcoidosis. All commonly administered immunosuppressive treatment strategies in rheumatology can be used for non-infectious forms in addition to local and regional forms of treatment. The diagnostic and therapeutic impulses of this interdisciplinary interface between rheumatology and ophthalmology is discussed in more detail in this article.

Determination of the solid angle and response function of a hemispherical spectrograph with injection lens for Auger electrons emitted from long lived projectile states.

We present SIMION 8.1 Monte Carlo type simulations of the response function and detection solid angle for long lived Auger states (lifetime τ ∼ 10(-9) - 10(-5) s) recorded by a hemispherical spectrograph with injection lens and position sensitive detector used for high resolution Auger spectroscopy of ion beams. Also included in these simulations for the first time are kinematic effects particular to Auger emission from fast moving projectile ions such as line broadening and solid angle limitations allowing for a more accurate and realistic line shape modeling. Our results are found to be in excellent agreement with measured electron line shapes of both long lived 1s2s2p(4)P and prompt Auger projectile states formed by electron capture in collisions of 25.3 MeV F(7+) with H2 and 12.0 MeV C(4+) with Ne recorded at 0° to the beam direction. These results are important for the accurate evaluation of the 1s2s2p (4)P/(2)P ratio of K-Auger cross sections whose observed non-statistical production by electron capture into He-like ions, recently a field of interesting interpretations, awaits further resolution.

Influence of high-density lipoprotein and paraoxonase-1 on platelet reactivity in patients with acute coronary syndromes receiving clopidogrel therapy.

BACKGROUND: The paraoxonase activity of the enzyme paraoxonase-1 (PON-1) associated with high-density lipoprotein (HDL) may significantly influence clopidogrel's antiplatelet and clinical efficacy as a result of its involvement in the clopidogrel biotransformation to the pharmacologically active thiol metabolite. We evaluated the possible relationships of HDL levels as well as PON-1 activities and the Q192R genotype with clopidogrel's antiplatelet efficacy in acute coronary syndrome (ACS) patients. METHODS AND RESULTS: The platelet aggregation, P-selectin expression and platelet/leukocyte conjugates as well as the clopidogrel response variability (evaluated by the VASP phosphorylation test and expressed as platelet reactivity index, PRI) were assessed in 74 ACS patients undergoing percutaneous coronary intervention (PCI) in relation to the PON-1 Q192R genotype and to serum HDL-cholesterol levels, and PON-1 (paraoxonase and arylesterase) activities. Patients were loaded with 600 mg of clopidogrel followed by 75 mg per day. HDL-cholesterol levels and PON-1 activities at baseline (before clopidogrel loading) were not altered at 5- and 30-day post-clopidogrel loading, whereas baseline platelet activation parameters were significantly attenuated. At 5 days, 17 patients were clopidogrel non-responders (PRI: 64.2 ± 11.1%). HDL-cholesterol was inversely associated with platelet activation parameters independently on platelet response variability to clopidogrel whereas a negative association between platelet activation parameters and paraoxonase activity was observed in patients adequately responding to clopidogrel but not in clopidogrel non-responders. Similarly, the platelet activation markers were significantly higher in PON-1 Q192Q genotype carriers compared with those having one or two R alleles only in patients adequately responding to clopidogrel. CONCLUSIONS: PON-1 is an important determinant of clopidogrel antiplatelet efficacy only in patients adequately responding to clopidogrel. These findings may be clinically important in ACS patients receiving clopidogrel therapy, especially the first days after the episode.

Allergic reactions during allergy skin testing with food allergens.

Skin testing is a reliable and safe way to diagnose IgE-mediated allergies, with rare side-effects. Two cases of systemic allergic reactions during skin testing to food allergens are hereby reported. A 28-year-old male reported allergic reactions, mild to moderate in severity, each time he tasted fish in the frame of his professional duties. During SPT and prick-to-prick to raw and cooked fishes, he presented urticaria and tachycardia. A 59-year-old male had a long history of urticaria-angioedema and asthma attacks, following the consumption of mammalian meat. He was skin-tested to various meats and during the 5 last minutes of the test he developed generalized urticaria, allergic rhinitis and conjunctivitis. They were both advised to completely avoid the relative allergens. In conclusion, skin testing, particularly prick-to-prick, may cause anaphylaxis. Tests should be performed only by physicians with proper training in allergy, experienced in treating promptly and properly episodes of anaphylaxis.

Peritoneal membrane transport for low molecular weight substances with the use of one bag dialysate collection.

The 24-hour collection of dialysate provides an accurate method for evaluation of both adequacy of dialysis and peritoneal membrane transport characteristics in patients on chronic ambulatory peritoneal dialysis. However, this test requires 24 hours to complete and therefore it is inconvenient for both patients and nurses in the every day practice. We determined the peritoneal membrane transport characteristics for low molecular weight substances of ten patients by using the dialysate collection of only one bag. Dialysate/plasma creatinine ratios were calculated for each of the 4 bags (DATT1, DATT2, DATT3, DATT4) as well as for the 24 hour dialysate (DATTo). We found a very good correlation between DATTo and the four DATTs. We therefore propose that the evaluation of the peritoneal membrane transport, at least for creatinine could be determined with the use of one bag dialysate collection.

Death during deliberate propane inhalation.

Propane gas is used as a fuel and very rarely it is abused by young people in Greece. In this paper, we report a case of abuse of propane inhalation that resulted in accidental death. The determination of propane in autopsy samples was done by headspace gas chromatography and semiquantitation in liver, blood and the contents of the plastic bag through which the gas was diffused, which proved to be lethal.

Personal and environmental air sampling of methyl bromide during experimental greenhouse fumigation.

In this investigation methyl bromide, a widely used soil fumigant, was investigated with respect to workers exposure and environmental fortification at the greenhouses of Thessaloniki area, Northern Greece. By means of personal and environmental air sampling through charcoal, methyl bromide concentration was measured by gas chromatography using a capillary OV-1 column at 45 degrees C and flame ionization detector (FID). Personal air sampling for two workers showed that the levels of exposure to methyl bromide were 89 and 92 mg/m3 respectively. These values exceeded the safety limits. The mean maximum and mean minimum concentrations in the environmental air samples inside the greenhouse, for 8 hours duration, were 142 mg/m3 and 4 mg/m3, respectively. These concentrations were determined within four and eleven days after the application of methyl bromide.

Immunohistochemical detection of the melanocortin 1 receptor in human testis, ovary and placenta using specific monoclonal antibody.

We describe the immunohistochemical detection of the melanocortin 1 receptor (MC1R) protein in human gonadal tissues using a specific monoclonal antibody. The MC1R was found to be present in Leydig's cells in testis, in lutein cells in the corpus luteum and in the nucleus of the trophoblastic cells of the placenta. Though it has been speculated earlier that MC1R is present in gonadal tissues, this is the first report demonstrating the presence of MC1R protein in these cells.

Moisture sorption profiles and tensile strength of tableted phenobarbitone formulations.

The tensile strength of tablets made from phenobarbitone and sodium phenobarbitone formulations after storage at increasing ambient relative humidity has been investigated. The moisture sorption and desorption profiles of the formulations were analysed for three locations of moisture: monolayer adsorbed moisture, normally condensed moisture and absorbed moisture. Maxima in tensile strength occur at moisture distributions determined by the disintegrant used. The changes in tensile strength have been explained in terms of changes produced in the interparticle separation, the range of the interparticle forces and changes in the ratio of the binding to diffusional forces, acting on the water molecules which are on the particles' surface.