Point mutations in the stem region and the fourth AAA domain of cytoplasmic dynein heavy chain partially suppress the phenotype of NUDF/LIS1 loss in Aspergillus nidulans

Cytoplasmic dynein performs multiple cellular tasks but its regulation remains unclear. The dynein heavy chain has a N-terminal stem that binds to other subunits and a C-terminal motor unit that contains six AAA (ATPase associated with cellular activities) domains and a microtubule-binding site located between AAA4 and AAA5. In Aspergillus nidulans, NUDF (a LIS1 homolog) functions in the dynein pathway, and two nudF6 partial suppressors were mapped to the nudA dynein heavy chain locus. Here we identified these two mutations. The nudAL1098F mutation resides in the stem region, and nudAR3086C is in the end of AAA4. These mutations partially suppress the phenotype of nudF deletion but do not suppress the phenotype exhibited by mutants of dynein intermediate chain and Arp1. Surprisingly, the stronger DeltanudF suppressor, nudAR3086C, causes an obvious decrease in the basal level of dynein's ATPase activity and an increase in dynein's distribution along microtubules. Thus, suppression of the DeltanudF phenotype may result from mechanisms other than simply the enhancement of dynein's ATPase activity. The fact that a mutation in the end of AAA4 negatively regulates dynein's ATPase activity but partially compensates for NUDF loss indicates the importance of the AAA4 domain in dynein regulation in vivo.

Ventilation-perfusion ratio in perflubron during partial liquid ventilation

BACKGROUND: Functional magnetic resonance imaging (fMRI) of fluorine-19 allows for the mapping of oxygen partial pressure within perfluorocarbons in the alveolar space (Pao(2)). Theoretically, fMRI-detected Pao(2) can be combined with the Fick principle approach, i.e., a mass balance of oxygen uptake by ventilation and delivery by perfusion, to quantify the ventilation-perfusion ratio (Va/Q) of a lung region: The mixed venous blood and the inspiratory oxygen fraction, which are equal for all lung regions, are measured. In addition, the local expiratory oxygen fraction and the end capillary oxygen content, both of which may differ between the lung regions, are calculated using the fMRI-detected Pao(2). We investigated this approach by numerical simulations and applied it to quantify local Va/Q in the perfluorocarbons during partial liquid ventilation. METHODS: Numerical simulations were performed to analyze the sensitivity of the Va/Q calculation and to compare this approach with another one proposed by Rizi et al. in 2004 (Magn Reson Med 2004;52:65-72). Experimentally, the method was used during partial liquid ventilation in 7 anesthetized pigs. The Pao(2) distribution in intraalveolar perflubron was measured by fluorine-19 MRI. Respiratory gas fractions together with arterial and mixed venous blood samples were taken to quantify oxygen partial pressure and content. Using the Fick principle, the local Va/Q was estimated. The impact of gravity (nondependent versus dependent) of perflubron dose (10 vs 20 mL/kg body weight) and of inspired oxygen fraction (Fio(2)) (0.4-1.0) on Va/Q was examined. RESULTS: In numerical simulations, the Fick principle proved to be appropriate over the Va/Q range from 0.02 to 2.5. Va/Q values were in acceptable agreement with the method published by Rizi et al. In the experimental setting, low mean Va/Q values were found in perflubron (confidence interval [CI] 0.08-0.29 with 20 mL/kg perflubron). At this dose, Va/Q in the nondependent lung was higher (CI 0.18-0.39) than in the dependent lung regions (CI 0.06-0.16; P = 0.006; Student t test). Differences depending on Fio(2) or perflubron dose were, however, small. CONCLUSION: The results show that derivation of Va/Q from local Po(2) measurements using fMRI in perflubron is feasible. The low detected Va/Q suggests that oxygen transport into the perflubron-filled alveolar space is significantly restrained.

[Partial clinical remission of chronic IgA nephropathy with therapy of tuberculosis]

A 36-year-old patient suffered from repeated exsudative pleural effusions and renal insufficiency (serum creatinine 1.9 mg/dl) combined with glomerular erythrocyturia, proteinuria and renal hypertension.

Identification of serotonin 5-HT1A receptor partial agonists in ginger

Animal studies suggest that ginger (Zingiber officinale Roscoe) reduces anxiety. In this study, bioactivity-guided fractionation of a ginger extract identified nine compounds that interact with the human serotonin 5-HT(1A) receptor with significant to moderate binding affinities (K(i)=3-20 microM). [(35)S]-GTP gamma S assays indicated that 10-shogaol, 1-dehydro-6-gingerdione, and particularly the whole lipophilic ginger extract (K(i)=11.6 microg/ml) partially activate the 5-HT(1A) receptor (20-60% of maximal activation). In addition, the intestinal absorption of gingerols and shogaols was simulated and their interactions with P-glycoprotein were measured, suggesting a favourable pharmacokinetic profile for the 5-HT(1A) active compounds.

Knowing the future: partial foreknowledge effects on the programming of prosaccades and antisaccades

Foreknowledge about the demands of an upcoming trial may be exploited to optimize behavioural responses. In the current study we systematically investigated the benefits of partial foreknowledge--that is, when some but not all aspects of a future trial are known in advance. For this we used an ocular motor paradigm with horizontal prosaccades and antisaccades. Predictable sequences were used to create three partial foreknowledge conditions: one with foreknowledge about the stimulus location only, one with foreknowledge about the task set only, and one with foreknowledge about the direction of the required response only. These were contrasted with a condition of no-foreknowledge and a condition of complete foreknowledge about all three parameters. The results showed that the three types of foreknowledge affected saccadic efficiency differently. While foreknowledge about stimulus-location had no effect on efficiency, task foreknowledge had some effect and response-foreknowledge was as effective as complete foreknowledge. Foreknowledge effects on switch costs followed a similar pattern in general, but were not specific for switching of the trial attribute for which foreknowledge was available. We conclude that partial foreknowledge has a differential effect on efficiency, most consistent with preparatory activation of a motor schema in advance of the stimulus, with consequent benefits for both switched and repeated trials.

Vasculitides associated with IgG antineutrophil cytoplasmic autoantibodies in childhood

Immunoglobulin (Ig)G antineutrophil cytoplasmic autoantibodies are causally associated with necrotizing vasculitides that are characterized immunopathologically by little or no deposition of immunoreactants, such as Wegener granulomatosis, microscopic polyangiitis, Churg-Strauss angiitis, "renal-limited" vasculitis and a number of drug-induced vasculitides. Clinical routine testing targets the antigens myeloperoxidase and proteinase 3. However, in all of the conditions mentioned, the renal histopathologic findings are indistinguishable. Churg-Strauss angiitis (characterized by necrotizing vasculitis, granulomatous inflammation and tissue eosinophilia), Wegener granulomatosis (characterized by necrotizing vasculitis and granulomatous inflammation) and microscopic polyangiitis (characterized by necrotizing vasculitis) often present with fever, weight loss and a multisystem involvement (ear, nose, throat, lung, eyes, peripheral nerve and heart). Fifty years ago these conditions were very often fatal within 6 months of diagnosis. The introduction of corticosteroids and cyclophosphamide has resulted in a dramatic clinical benefit. Patients who develop treatment-related morbidity can be switched from cyclophosphamide to azathioprine after achieving remission. In patients with less severe disease, methotrexate achieves remission with a success rate similar to that of cyclophosphamide. Plasma exchange, in association with immunosuppression, is likely to be a beneficial therapy for patients with severe kidney disease or pulmonary hemorrhage.

Microbiologic findings 1 year after partial- and full-mouth scaling in the treatment of moderate chronic periodontitis

To investigate the impact on microbiologic variables of full-mouth scaling (FMS) and conventional scaling and root planing (cSRP) after 12 months.

High-level cytoplasmic cyclin D1 expression in lymph node metastases from prostate cancer independently predicts early biochemical failure and death in surgically treated patients

To test the prognostic significance of cyclin D1 in nodal-positive prostate cancer.

Intraoperative Patient-Specific Reconstruction of Partial Bone Flap Defects After Convexity Meningioma Resection

OBJECTIVE: To evaluate implant accuracy and cosmetic outcome of a new intraoperative patient-specific cranioplasty method after convexity meningioma resection. METHODS: The patient's own bone flap served as a template to mold a negative form with the use of polymethyl methacrylate (PMMA). The area of bone invasion was determined and broadly excised under white light illumination with a safety margin of at least 1 cm. The definitive replica was cast within the remaining bone flap frame and the imprint. Clinical and radiologic follow-up examinations were performed 3 months after surgery. RESULTS: Four women and two men (mean age 51.4 years ± 12.8) underwent reconstruction of bone flap defects after meningioma resection. Mean duration of intraoperative reconstruction of the partial bone flap defects was 19 minutes ± 4 (range 14-24 minutes). Implant sizes ranged from 17-35 cm(2) (mean size 22 cm(2) ± 8). Radiologic and clinical follow-up examinations revealed excellent implant alignment and favorable cosmesis (visual analogue scale for cosmesis [VASC] = 97 ± 5) in all patients. CONCLUSIONS: Patient-specific reconstruction of partial bone flap defects after convexity meningioma resection using the presented intraoperative PMMA cast method resulted in excellent bony alignment and a favorable cosmetic outcome. Relatively low costs and minimized operation time for adjustment and insertion of the cranioplasty implant justify use of this method in small bony defects as well.

Alba-domain proteins of Trypanosoma brucei are cytoplasmic RNA-binding proteins that interact with the translation machinery

Trypanosoma brucei and related pathogens transcribe most genes as polycistronic arrays that are subsequently processed into monocistronic mRNAs. Expression is frequently regulated post-transcriptionally by cis-acting elements in the untranslated regions (UTRs). GPEET and EP procyclins are the major surface proteins of procyclic (insect midgut) forms of T. brucei. Three regulatory elements common to the 3' UTRs of both mRNAs regulate mRNA turnover and translation. The glycerol-responsive element (GRE) is unique to the GPEET 3' UTR and regulates its expression independently from EP. A synthetic RNA encompassing the GRE showed robust sequence-specific interactions with cytoplasmic proteins in electromobility shift assays. This, combined with column chromatography, led to the identification of 3 Alba-domain proteins. RNAi against Alba3 caused a growth phenotype and reduced the levels of Alba1 and Alba2 proteins, indicative of interactions between family members. Tandem-affinity purification and co-immunoprecipitation verified these interactions and also identified Alba4 in sub-stoichiometric amounts. Alba proteins are cytoplasmic and are recruited to starvation granules together with poly(A) RNA. Concomitant depletion of all four Alba proteins by RNAi specifically reduced translation of a reporter transcript flanked by the GPEET 3' UTR. Pulldown of tagged Alba proteins confirmed interactions with poly(A) binding proteins, ribosomal protein P0 and, in the case of Alba3, the cap-binding protein eIF4E4. In addition, Alba2 and Alba3 partially cosediment with polyribosomes in sucrose gradients. Alba-domain proteins seem to have exhibited great functional plasticity in the course of evolution. First identified as DNA-binding proteins in Archaea, then in association with nuclear RNase MRP/P in yeast and mammalian cells, they were recently described as components of a translationally silent complex containing stage-regulated mRNAs in Plasmodium. Our results are also consistent with stage-specific regulation of translation in trypanosomes, but most likely in the context of initiation.

Partial tetraplegic syndrome as a complication of a mobilizing/manipulating procedure of the cervical spine in a man with Forestier's disease: a case report

Introduction Even if performed by qualified physical therapists, spinal manipulation and mobilization can cause adverse events. This holds true particularly for the cervical spine. In light of the substantial risks, the benefits of cervical spine manipulation may be outweighed by the possibility of further injury. Case presentation We present the case of a 56-year-old Caucasian man with Forestier's disease who went to see a physiotherapist to relieve his aching neck while on a holiday trip. Following the procedure, he was transferred to a local hospital with a partial tetraplegic syndrome due to a cervical 6/7 luxation fracture. Reportedly, the physiotherapist took neither a detailed history, nor adequate diagnostic measures. Conclusions This case highlights the potentially dangerous complications associated with cervical spine mobilization/manipulation. If guidelines concerning cervical spine mobilization and manipulation practices had been followed, this adverse event could have been avoided.

Quantitative mapping of T2 using partial spoiling

Fast quantitative MRI has become an important tool for biochemical characterization of tissue beyond conventional T1, T2, and T2*-weighted imaging. As a result, steady-state free precession (SSFP) techniques have attracted increased interest, and several methods have been developed for rapid quantification of relaxation times using steady-state free precession. In this work, a new and fast approach for T2 mapping is introduced based on partial RF spoiling of nonbalanced steady-state free precession. The new T2 mapping technique is evaluated and optimized from simulations, and in vivo results are presented for human brain at 1.5 T and for human articular cartilage at 3.0 T. The range of T2 for gray and white matter was from 60 msec (for the corpus callosum) to 100 msec (for cortical gray matter). For cartilage, spatial variation in T2 was observed between deep (34 msec) and superficial (48 msec) layers, as well as between tibial (33 msec), femoral, (54 msec) and patellar (43 msec) cartilage. Excellent correspondence between T2 values derived from partially spoiled SSFP scans and the ones found with a reference multicontrast spin-echo technique is observed, corroborating the accuracy of the new method for proper T2 mapping. Finally, the feasibility of a fast high-resolution quantitative partially spoiled SSFP T2 scan is demonstrated at 7.0 T for human patellar cartilage.

Deletion of P399_E401 in NADPH cytochrome P450 oxidoreductase results in partial mixed oxidase deficiency

P450 oxidoreductase (POR) is the electron donor for all microsomal P450s including steroidogenic enzymes CYP17A1, CYP19A1 and CYP21A2. We found a novel POR mutation P399_E401del in two unrelated Turkish patients with 46,XX disorder of sexual development. Recombinant POR proteins were produced in yeast and tested for their ability to support steroid metabolizing P450 activities. In comparison to wild-type POR, the P399_E401del protein was found to decrease catalytic efficiency of 21-hydroxylation of progesterone by 68%, 17α-hydroxylation of progesterone by 76%, 17,20-lyase action on 17OH-pregnenolone by 69%, aromatization of androstenedione by 85% and cytochrome c reduction activity by 80%. Protein structure analysis of the three amino acid deletion P399_E401 revealed reduced stability and flexibility of the mutant. In conclusion, P399_E401del is a novel mutation in POR that provides valuable genotype-phenotype and structure-function correlation for mutations in a different region of POR compared to previous studies. Characterization of P399_E401del provides further insight into specificity of different P450s for interaction with POR as well as nature of metabolic disruptions caused by more pronounced effect on specific P450s like CYP17A1 and aromatase.

A novel GH-1 gene mutation (GH-P59L) causes partial GH deficiency type II combined with bioinactive GH syndrome

Despite the differences in the main characteristics between the autosomal dominant form of GH deficiency (IGHD II) and the bioinactive GH syndrome, a common feature of both is their impact on linear growth leading to short stature in all affected patients.