Sertraline-Induced Sleep Paralysis: A Case Report.

Major depressive disorder (MDD) is associated with both insomnia and hypersomnia, but it predominantly decreases sleep continuity and leads to a decrease in rapid eye movement (REM) latency, an increase in REM sleep duration, and an increase in REM density. Some of these changes persist even when MDD is treated and can be associated with a recurrence of MDD. Antidepressants can potentially complicate the relationship between REM sleep and depression, as a majority of patients report improved sleep when prescribed selective serotonin reuptake inhibitors (SSRIs) but some case reports mention that SSRIs have been associated with REM inhibition, resulting in decreased REM sleep. We present a case report of a young patient with MDD who started experiencing multiple episodes of distressing sleep paralysis after he started taking sertraline and resolved as he was tapered off the medication. Through references from the literature indicating a potential link between parasomnias and SSRIs, we were able to discuss that SSRIs can potentially lead to isolated sleep paralysis and should be considered as an uncommon yet distressing side effect although not listed in the package insert. Isolated sleep paralysis has been defined in the literature as the inability to perform voluntary movements of the trunk and all limbs for a period of seconds to minutes at the beginning of sleep or upon waking up. Further research is needed to clarify the impact of SSRIs on sleep and practice guidelines should be clarified in regard to their role.

A Case of Olanzapine-Induced Cutaneous Eruption.

BACKGROUND Different medication classes have been implicated in cutaneous eruptions that may lead to significant morbidity and mortality. In drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, the patient may initially present with a cutaneous eruption and hematologic abnormalities which can lead to acute visceral organ involvement if the offending drug is not discontinued. There is also a potential for long-term sequelae such as autoimmune disorders. CASE REPORT A 47-year-old woman with an unknown past medical history and no known drug allergies was admitted to the Behavioral Health Unit, where she was diagnosed with disorganized schizophrenia and started on olanzapine. On day 17 of admission, she developed a diffuse, macular, and erythematous rash on her abdomen, which spread to involve over 50% of her total body surface area. Occipital and posterior auricular lymphadenopathy was present. The patient was treated with prednisone and diphenhydramine. Olanzapine was subsequently discontinued and the patient's rash cleared up. CONCLUSIONS This case report highlights the challenges in diagnosing DRESS syndrome and the potential for antipsychotics to cause DRESS syndrome. DRESS syndrome is a clinical diagnosis augmented by laboratory tests with a wide range of patient presentations. Although there are probability criteria to assist with diagnosis, not all patients will fall exactly into these criteria, which can lead to missed diagnoses and poor patient outcomes. A challenge with DRESS syndrome diagnosis is the latency period between drug initiation and cutaneous eruption. Thus, in differential diagnoses for skin eruptions, temporal associations (minutes, days, weeks) with medications are crucial.

Pregnancy Outcomes in Late Onset Pompe Disease.

There is limited data on pregnancy outcomes in Pompe Disease (PD) resulting from deficiency of the lysosomal enzyme acid alpha-glucosidase. Late-onset PD is characterized by progressive proximal muscle weakness and decline of respiratory function secondary to the involvement of the respiratory muscles. In a cohort of twenty-five females, the effects of both PD on the course of pregnancy and the effects of pregnancy on PD were investigated. Reproductive history, course of pregnancy, use of Enzyme replacement therapy (ERT), PD symptoms, and outcomes of each pregnancy were obtained through a questionnaire. Among 20 subjects that reported one or more pregnancies, one subject conceived while on ERT and continued therapy through two normal pregnancies with worsening of weakness during pregnancy and improvement postpartum. While fertility was not affected, pregnancy may worsen symptoms, or cause initial symptoms to arise. Complications with pregnancy or birth were not higher, except for an increase in the rate of stillbirths (3.8% compared to the national average of 0.2-0.7%). Given small sample size and possible bias of respondents being only women who have been pregnant, further data may be needed to better analyze the effects of pregnancy on PD, and the effects of ERT on pregnancy outcomes.

Structural insight into the quinolone-DNA cleavage complex of type IIA topoisomerases.

Type II topoisomerases alter DNA topology by forming a covalent DNA-cleavage complex that allows DNA transport through a double-stranded DNA break. We present the structures of cleavage complexes formed by the Streptococcus pneumoniae ParC breakage-reunion and ParE TOPRIM domains of topoisomerase IV stabilized by moxifloxacin and clinafloxacin, two antipneumococcal fluoroquinolones. These structures reveal two drug molecules intercalated at the highly bent DNA gate and help explain antibacterial quinolone action and resistance.

The difficult case of crystallization and structure solution for the ParC55 breakage-reunion domain of topoisomerase IV from Streptococcus pneumoniae.

BACKGROUND: Streptococcus pneumoniae is the major cause of community-acquired pneumonia and is also associated with bronchitis, meningitis, otitis and sinusitis. The emergence and increasing prevalence of resistance to penicillin and other antibiotics has led to interest in other anti-pneumonococcal drugs such as quinolones that target the enzymes DNA gyrase and topoisomerase IV. During crystallization and in the avenues to finding a method to determine phases for the structure of the ParC55 breakage-reunion domain of topoisomerase IV from Streptococcus pneumoniae, obstacles were faced at each stage of the process. These problems included: majority of the crystals being twinned, either non-diffracting or exhibiting a high mosaic spread. The crystals, which were grown under conditions that favoured diffraction, were difficult to flash-freeze without loosing diffraction. The initial structure solution by molecular replacement failed and the approach proved to be unviable due to the complexity of the problem. In the end the successful structure solution required an in-depth data analysis and a very detailed molecular replacement search. METHODOLOGY/PRINCIPAL FINDINGS: Crystal anti-twinning agents have been tested and two different methods of flash freezing have been compared. The fragility of the crystals did not allow the usual method of transferring the crystals into the heavy atom solution. Consequently, it was necessary to co-crystallize in the presence of the heavy atom compound. The multiple isomorphous replacement approach was unsuccessful because the 7 cysteine mutants which were engineered could not be successfully derivatized. Ultimately, molecular replacement was used to solve the structure by sorting through a large number of solutions in space group P1 using CNS. CONCLUSIONS/SIGNIFICANCE: The main objective of this paper is to describe the obstacles which were faced and overcome in order to acquire data sets on such difficult crystals and determine phases for successful structure solution.

Breakage-reunion domain of Streptococcus pneumoniae topoisomerase IV: crystal structure of a gram-positive quinolone target.

The 2.7 A crystal structure of the 55-kDa N-terminal breakage-reunion domain of topoisomerase (topo) IV subunit A (ParC) from Streptococcus pneumoniae, the first for the quinolone targets from a gram-positive bacterium, has been solved and reveals a 'closed' dimer similar in fold to Escherichia coli DNA gyrase subunit A (GyrA), but distinct from the 'open' gate structure of Escherichia coli ParC. Unlike GyrA whose DNA binding groove is largely positively charged, the DNA binding site of ParC exhibits a distinct pattern of alternating positively and negatively charged regions coincident with the predicted positions of the grooves and phosphate backbone of DNA. Based on the ParC structure, a new induced-fit model for sequence-specific recognition of the gate (G) segment by ParC has been proposed. These features may account for the unique DNA recognition and quinolone targeting properties of pneumococcal type II topoisomerases compared to their gram-negative counterparts.

Database searching for thymidine and thymidylate kinase inhibitors using three-dimensional structure-based methods.

Structure-based drug design methods were used to search for novel inhibitors of herpes simplex virus type 1 (HSV-1) thymidine kinase and Mycobacterium tuberculosis thymidylate kinase. The method involved the use of crystal structure complexes to guide database searching for potential inhibitors. A number of weak inhibitors of HSV-2 were identified, one of which was found to inhibit HSV-1 TK and HSV-1 TK-deficient viral strains. Each compound tested against M. tuberculosis thymidylate kinase was found to have some activity. The best of these compounds was only 4.6-fold less potent than 3'-azido-3'-deoxythymidine-5'-monophosphate (AZTMP). This study demonstrates the utility of structure-based drug design methods in the search for novel enzyme inhibitors.

The crystal structure of IgE Fc reveals an asymmetrically bent conformation.

The distinguishing structural feature of immunoglobulin E (IgE), the antibody responsible for allergic hypersensitivity, is the C epsilon 2 domain pair that replaces the hinge region of IgG. The crystal structure of the IgE Fc (constant fragment) at a 2.6-A resolution has revealed these domains. They display a distinctive, disulfide-linked Ig domain interface and are folded back asymmetrically onto the C epsilon 3 and C epsilon 4 domains, which causes an acute bend in the IgE molecule. The structure implies that a substantial conformational change involving C epsilon 2 must accompany binding to the mast cell receptor Fc epsilon RI. This may be the basis of the exceptionally slow dissociation rate of the IgE-Fc epsilon RI complex and, thus, of the ability of IgE to cause persistent allergic sensitization of mast cells.