Automorphism groups of countable algebraically closed graphs and endomorphisms of the random graph

We establish links between countable algebraically closed graphs and the endomorphisms of the countable universal graph $R$. As a consequence we show that, for any countable graph $\Gamma$, there are uncountably many maximal subgroups of the endomorphism monoid of $R$ isomorphic to the automorphism group of $\Gamma$. Further structural information about End $R$ is established including that Aut $\Gamma$ arises in uncountably many ways as a Sch\"{u}tzenberger group. Similar results are proved for the countable universal directed graph and the countable universal bipartite graph.Comment: Minor revision following referee's comments. 27 pages, 3 figure

Intention tremor in essential tremor : prevalence and association with disease duration

Scholarly attention only recently has been focused on intention tremor (IT) in essential tremor (ET).1, 2 Therefore, little has been written on its prevalence or clinical correlates. The association between IT and disease duration also remains unsettled. This question has pathophysiological implications. Studies have indicated metabolic and structural changes in the ET cerebellum.3, 4 If ET were a disease of progressive cerebellar dysregulation, one would expect more IT in patients with disease of longer duration. We assessed the prevalence and clinical correlates of IT and determined whether there was an association between IT and disease duration

Essential tremor associated with pathologic changes in the cerebellum

Background: Although essential tremor (ET) is one of the most common neurologic disorders, there have been few postmortem studies. We recently reported postmortem changes (torpedoes and Bergmann gliosis) in the cerebellar cortex in a few ET cases. Objective: To describe more extensive postmortem changes in the cerebellum in another ET case. Design: Case report. Results: A 90-year-old woman had a 30-year history of ET. At postmortem examination, there was segmental loss of Purkinje cells, presence of torpedoes, and Bergmann gliosis in the cerebellar cortex. Moreover, there were extensive changes in the dentate nucleus, in the form of neuronal loss, neuronal atrophy, microglial clusters, and reduction in the number of efferent fibers (ie, pallor of the hilum). Conclusions: The brain in the current case exhibited more marked cerebellar pathologic features than noted in previously reported ET cases and thereby extends the described cerebellar findings in this common, yet pathologically poorly characterized, neurologic disorder

Ramified rectilinear polygons: coordinatization by dendrons

Simple rectilinear polygons (i.e. rectilinear polygons without holes or cutpoints) can be regarded as finite rectangular cell complexes coordinatized by two finite dendrons. The intrinsic $l_1$-metric is thus inherited from the product of the two finite dendrons via an isometric embedding. The rectangular cell complexes that share this same embedding property are called ramified rectilinear polygons. The links of vertices in these cell complexes may be arbitrary bipartite graphs, in contrast to simple rectilinear polygons where the links of points are either 4-cycles or paths of length at most 3. Ramified rectilinear polygons are particular instances of rectangular complexes obtained from cube-free median graphs, or equivalently simply connected rectangular complexes with triangle-free links. The underlying graphs of finite ramified rectilinear polygons can be recognized among graphs in linear time by a Lexicographic Breadth-First-Search. Whereas the symmetry of a simple rectilinear polygon is very restricted (with automorphism group being a subgroup of the dihedral group $D_4$), ramified rectilinear polygons are universal: every finite group is the automorphism group of some ramified rectilinear polygon.Comment: 27 pages, 6 figure

Risk of Parkinson disease in carriers of parkin mutations : estimation using the kin-cohort method

Objective: To estimate the risk of Parkinson disease (PD) in individuals with mutations in the Parkin gene. Design: We assessed point mutations and exon deletions and duplications in the Parkin gene in 247 probands with PD (age at onset 50 years) and 104 control probands enrolled in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. For each first-degree relative, a consensus diagnosis of PD was established. The probability that each relative carried a mutation was estimated from the proband's Parkin carrier status using Mendelian principles and from the relationship of the relative to the proband. Setting: Tertiary care movement disorders center. Patients: Cases, controls, and their first-degree relatives were enrolled in the GEPD study. Main Outcome Measures: Estimated age-specific penetrance in first-degree relatives. Results: Parkin mutations were identified in 25 probands with PD (10.1%), 18 (72.0%) of whom were heterozygotes. One Parkin homozygote was reported in 2 siblings with PD. The cumulative incidence of PD to age 65 years in carrier relatives (age-specific penetrance) was estimated to be 7.0% (95% confidence interval, 0.4%-71.9%), compared with 1.7% (95% confidence interval, 0.8%-3.4%) in noncarrier relatives of the cases (P = .59) and 1.1% (95% confidence interval, 0.3%-3.4%) in relatives of the controls (compared with noncarrier relatives, P = .52). Conclusions: The cumulative risk of PD to age 65 years in a noncarrier relative of a case with an age at onset of 50 years or younger is not significantly greater than the general population risk among controls. Age-specific penetrance among Parkin carriers, in particular heterozygotes, deserves further study. Mutations in the Parkin gene (PARK2; GenBank AB009973) are associated primarily with early-onset Parkinson disease (PD), defined as age at onset (AAO) ranging from 45 years or younger to 55 years or younger, but have also been described in PD cases with an AAO older than 70 years. In PD cases with an AAO of 45 years or younger with a mode of inheritance consistent with autosomal recessive transmission, the frequency of Parkin mutations may be as high as 49%, whereas in cases without a family history of PD the range is 15% to 18%. Age at onset is inversely correlated with the frequency of Parkin mutations in both familial and sporadic cases. Several studies have compared the AAO of PD in heterozygous, compound heterozygous, and homozygous Parkin mutation carriers and found that heterozygous cases, both familial and sporadic, have an older AAO. Heterozygous Parkin mutation carriers are more frequently reported among sporadic than familial cases. Information on the risk of PD in individuals who carry Parkin mutations in either the homozygous, compound heterozygous, or heterozygous state (or penetrance) is essential for genetic counseling. The penetrance of Parkin mutations has only been reported for isolated families. Most of the previous study designs sampled PD cases based on family history of PD, which would bias penetrance estimates upwards. To obtain an unbiased estimate of risk, a population-based random sample would be desirable, but Parkin mutations are so rare in the population that such a sample would have to be extremely large to obtain sufficient precision in penetrance estimates. To obtain unbiased estimates of the risk of PD in Parkin carriers despite the low population frequency of Parkin mutations, we used a kin-cohort study design applied to participants in the Genetic Epidemiology of Parkinson's Disease (GEPD) study. The kin-cohort design is highly efficient for estimating penetrance because the relatives' mutation status is not required for the analyses, thus reducing costs for genetic analysis

Case-control study of the parkin gene in early-onset Parkinson disease

Background: Mutations in parkin are estimated to account for as much as 50% of familial Parkinson disease (PD) and 18% of sporadic PD. Single heterozygous mutations in parkin in both familial and sporadic cases may also increase susceptibility to PD. To our knowledge, all previous studies have been restricted to PD cases; this is the first study to systematically screen the parkin coding regions and exon deletions and duplications in controls. Objective: To determine the frequency and spectrum of parkin variants in early-onset PD cases (aged 50 years) and controls participating in a familial aggregation study. Patients and Methods: We sequenced the parkin gene in 101 cases and 105 controls. All cases and controls were also screened for exon deletions and duplications by semiquantitative multiplex polymerase chain reaction. Results: Thirteen (12.9% [95% confidence interval, 7%-21%]) of the 101 cases had a previously described parkin mutation: 1 was homozygous, 11 were heterozygous, and 1 was a compound heterozygote. The mutations Arg42Pro (exon 2) and Arg275Trp (exon 7) were recurrent. The previously reported synonymous substitution Leu261Leu (c.884A>G) was identified in 4 (3.9%) of 101 cases and 2 (2%) of 105 controls (P = .44). Excluding the synonymous substitution Leu261Leu (heterozygotes), 10 (9.9% [95% confidence interval, 4.6%-17.5%]) carried mutations. Conclusions: The frequency of mutations among cases that were not selected based on family history of PD is similar to what has previously been reported in sporadic PD. The similar frequency of Leu261Leu in cases and controls suggests it is a normal variant rather than a disease-associated mutation. We confirmed that heterozygous parkin mutations may increase susceptibility for early-onset PD

Tpl2 kinase regulates T cell interferon-γ production and host resistance to Toxoplasma gondii

Tpl2 (Tumor progression locus 2), also known as Cot/MAP3K8, is a hematopoietically expressed serine-threonine kinase. Tpl2 is known to have critical functions in innate immunity in regulating tumor necrosis factor–α, Toll-like receptor, and G protein–coupled receptor signaling; however, our understanding of its physiological role in T cells is limited. We investigated the potential roles of Tpl2 in T cells and found that it was induced by interleukin-12 in human and mouse T cells in a Stat4-dependent manner. Deficiency of Tpl2 was associated with impaired interferon (IFN)-γ production. Accordingly, Tpl2−/− mice had impaired host defense against Toxoplasma gondii with reduced parasite clearance and decreased IFN-γ production. Furthermore, reconstitution of Rag2−/− mice with Tpl2-deficient T cells followed by T. gondii infection recapitulated the IFN-γ defect seen in the Tpl2-deficient mice, confirming a T cell–intrinsic defect. CD4+ T cells isolated from Tpl2−/− mice showed poor induction of T-bet and failure to up-regulate Stat4 protein, which is associated with impaired TCR-dependent extracellular signal-regulated kinase activation. These data underscore the role of Tpl2 as a regulator of T helper cell lineage decisions and demonstrate that Tpl2 has an important functional role in the regulation of Th1 responses

Idiopathic radiographic apical root resorption in wind instrument players

Root resorption of the permanent teeth involves an elaborate interaction among inflammatory cells resulting in loss of dental hard tissues. This report describes three clinical cases where idiopathic root resorption occurred in wind instrument playing patients. These patients produce adequate non-orthodontic forces, while playing their instruments, to expose their teeth to root resorbing force. Careful clinical monitoring of patients' teeth should be undertaken, as the additive effects of orthodontic treatment and musical habits are unknown

Motor phenotype of LRRK2 G2019S carriers in early-onset Parkinson disease

Objective: To determine the motor phenotype of LRRK2 G2019S mutation carriers. LRRK2 mutation carriers were previously reported to manifest the tremor dominant motor phenotype, which has been associated with slower motor progression and less cognitive impairment compared with the postural instability and gait difficulty (PIGD) phenotype. Design: Cross-sectional observational study. Setting: Thirteen movement disorders centers. Participants: Nine hundred twenty-five early-onset Parkinson disease cases defined as age at onset younger than 51 years. Main Outcome Measures: LRRK2 mutation status and Parkinson disease motor phenotype: tremor dominant or PIGD. Demographic information, family history of Parkinson disease, and the Unified Parkinson's Disease Rating Scale score were collected on all participants. DNA samples were genotyped for LRRK2 mutations (G2019S, I2020T, R1441C, and Y1699C). Logistic regression was used to examine associations of G2019S mutation status with motor phenotype adjusting for disease duration, Ashkenazi Jewish ancestry, levodopa dose, and family history of Parkinson disease. Results: Thirty-four cases (3.7%) (14 previously reported) were G2019S carriers. No other mutations were found. Carriers were more likely to be Ashkenazi Jewish (55.9% vs 11.9%; P < .001) but did not significantly differ in any other demographic or disease characteristics. Carriers had a lower tremor score (P = .03) and were more likely to have a PIGD phenotype (92.3% vs 58.9%; P = .003). The association of the G2019S mutation with PIGD phenotype remained after controlling for disease duration and Ashkenazi Jewish ancestry (odds ratio, 17.7; P < .001). Conclusion: Early-onset Parkinson disease G2019S LRRK2 carriers are more likely to manifest the PIGD phenotype, which may have implications for disease course

Anthrax Lethal Toxin Disrupts Intestinal Barrier Function and Causes Systemic Infections with Enteric Bacteria

A variety of intestinal pathogens have virulence factors that target mitogen activated protein kinase (MAPK) signaling pathways, including Bacillus anthracis. Anthrax lethal toxin (LT) has specific proteolytic activity against the upstream regulators of MAPKs, the MAPK kinases (MKKs). Using a murine model of intoxication, we show that LT causes the dose-dependent disruption of intestinal epithelial integrity, characterized by mucosal erosion, ulceration, and bleeding. This pathology correlates with an LT-dependent blockade of intestinal crypt cell proliferation, accompanied by marked apoptosis in the villus tips. C57BL/6J mice treated with intravenous LT nearly uniformly develop systemic infections with commensal enteric organisms within 72 hours of administration. LT-dependent intestinal pathology depends upon its proteolytic activity and is partially attenuated by co-administration of broad spectrum antibiotics, indicating that it is both a cause and an effect of infection. These findings indicate that targeting of MAPK signaling pathways by anthrax LT compromises the structural integrity of the mucosal layer, serving to undermine the effectiveness of the intestinal barrier. Combined with the well-described immunosuppressive effects of LT, this disruption of the intestinal barrier provides a potential mechanism for host invasion via the enteric route, a common portal of entry during the natural infection cycle of Bacillus anthracis