Recurrent <Emphasis Type="Italic">TP53</Emphasis> missense mutation in cancer patients of Arab descent

Hereditary cancer comprises more than 10% of all breast cancer cases. Identification of germinal mutations enables the initiation of a preventive program that can include early detection or preventive treatment and may also have a major impact on cancer therapy. Several recurrent mutations were identified in the BRCA1/2 genes in Jewish populations however, in other ethnic groups in Israel, no recurrent mutations were identified to date. Our group established panel sequencing in cancer patients to identify recurrent, founder, and new mutations in the heterogeneous and diverse populations in Israel, We evaluated five breast cancer patients of Arab descent diagnosed with cancer before the age of 50 years and identified the previously described TP53 mutation, c.541C>T, R181C (rs587782596), in two women from unrelated Arab families. The two probands were diagnosed with breast cancer at a young age (27 and 34 years) and had significant family history spanning a wide range of tumors (breast cancer (BC), papillary thyroid cancer, glioblastoma multiform (GBM), colon cancer and leukemia). The R181C variant is expected to disrupt p53 at the ASPP2 binding domain but not the DNA binding domain and is defined by Clinvar as likely pathogenic and in HGMD as disease mutation. We further tested 85 unrelated Arab cancer patients and father of a BC carrier patient for TP53 c.541C>T using a real time polymerase chain reaction (RT-PCR) approach and identified four additional carriers, two with BC one with lung cancer, and the father of a BC carrier patient, diagnosed with GBM. Another carrier suffering from BC was identified using a Myriad panel, suggesting a recurrent mutation in this population with a frequency of 5/42 (11.9%) of our selected BC patients. We suggest testing Arab women with a breast cancer at a young age, Arab patients with multiple malignancies, or with suggestive family history for TP53 c.541C>T.     

Misidentification of transthyretin and immunoglobulin variants by proteomics due to methyl lysine formation in formalin-fixed paraffin-embedded amyloid tissue

Proteomics is becoming the de facto gold standard for identifying amyloid proteins and is now used routinely in a number of centres. The technique is compound class independent and offers the added ability to identify variant and modified proteins. We re-examined proteomics results from a number of formalin-fixed paraffin-embedded amyloid samples, which were positive for transthyretin (TTR) by immunohistochemistry and proteomics, using the UniProt human protein database modified to include TTR variants. The amyloidogenic variant, V122I TTR, was incorrectly identified in 26/27 wild-type and non-V122I variant samples due to its close mass spectral similarity with the methyl lysine-modified WT peptide [126K_Me]105–127 (p.[146 K_Me]125–147) generated during formalin fixation. Similarly, the methyl lysine peptide, [50K_Me]43–59, from immunoglobulin lambda light chain constant region was also misidentified as arising from a rare myeloma-derived lambda variant V49I. These processing-derived modifications are not present in fresh cardiac tissue, non-fixed fat nor serum and do not materially affect the identification of amyloid proteins. They could result in the incorrect assignment of a variant, and this may have consequences for the immediate family who will require genetic counselling and potentially early clinical intervention. As proteomics becomes a routine clinical test for amyloidosis, it becomes important to be aware of potentially confounding issues such as formalin-mediated lysine methylation, and how these may influence diagnosis and possibly treatment.     

A new method to record and control for 2D-movement kinematics during functional magnetic resonance imaging (fMRI)

The recording of movement kinematics during functional magnetic resonance imaging (fMRI) experiments is complicated due to technical constraints of the imaging environment. Nevertheless, to study the functions of brain areas related to motor control, reliable and accurate records of movement trajectories and speed profiles are needed. We present a method designed to record and characterize the kinematic properties of drawing- and handwriting-like forearm movements during fMRI studies by recording pen stroke trajectories. The recording system consists of a translucent plastic board, a plastic pen containing fiber optics and a halogen light power source, a CCD camera, a video monitor and a PC with a video grabber card. Control experiments using a commercially available digitizer tablet have demonstrated the reliability of the data recorded during fMRI. Since the movement tracking signal is purely optical, there is no interaction with the MR (echoplanar) images. Thus, the method allows to obtain movement records with high spatial and temporal resolution which are suitable for the kinematic analysis of hand movements in fMRI studies.     

Platelet poor plasma serotonin level in delinquent adolescents diagnosed with conduct disorder

Objective

Accumulating data indicate the involvement of the serotonergic system in adolescent aggression. The aim of this study was to examine the platelet-poor plasma (PPP) serotonin (5-HT) levels among delinquent adolescent boys with conduct disorder (CD) in comparison with normal controls.

Method

PPP 5-HT levels were measured in 16 male delinquent CD adolescents from a correctional facility and in 14 normal male adolescent controls. Severity of aggressive behavior was assessed by the Child Behavior Checklist (CBCL) and the Overt Aggression Scale (OAS).

Results

Delinquent CD adolescents had higher PPP 5-HT levels (about 3-fold) than the normal controls (27.68 ± 32.29 vs. 7.76 ± 4.23 ng/ml, respectively, p = 0.027). In the delinquent CD adolescents a significant correlation was found between the PPP 5-HT levels and the CBCL and OAS aggressive scores (r = 0.68, p = 0.0034 and r = 0.59, p = 0.016, respectively).

Conclusions

Juvenile delinquency is associated with high PPP 5-HT levels. Modulation of 5-HT neurotransmission may have a role in the symptomatology and treatment of severe adolescent CD.     

Multifunctional neuroprotective derivatives of rasagiline as anti-alzheimer’s disease drugs

The recent therapeutic approach in which drug candidates are designed to possess diverse pharmacological properties and act on multiple targets has stimulated the development of the multimodal drugs, ladostigil (TV3326) [(N-propargyl-(3R) aminoindan-5yl)-ethyl methyl carbamate] and the newly designed multifunctional antioxidant iron chelator, M-30 (5-[N-methyl-N-propargylaminomethyl]-8-hydroxyquinoline). Ladostigil combines, in a single molecule, the neuro-protective/neurorestorative effects of the novel anti-Parkinsonian drug and selective monoamine oxidase (MAO)-B inhibitor, rasagiline (Azilect, Teva Pharmaceutical Co.) with the cholinesterase (ChE) inhibitory activity of rivastigmine. A second derivative of rasagiline, M-30 was developed by amalgamating the propargyl moiety of rasagiline into the skeleton of our novel brain permeable neuroprotective iron chelator, VK-28. Preclinical experiments showed that both compounds have anti-Alzheimer’s disease activities and thus, the clinical development is oriented toward treatment of this type of dementia. This review discusses the multimodal effects of two rasagiline-containing hybrid molecules, namely ladostigil and M-30, concerning their neuroprotective molecular mechanisms in vivo and in vitro, including regulation of amyloid precursor protein processing, activation of protein kinase C, and mitogen-activated protein kinase signaling pathways, inhibition of cell death markers and upregulation of neurotrophic factors. Altogether, these scientific findings make these multifunctional compounds potentially valuable drugs for the treatment of Alzheimer’s disease.     

Evaluation of the <Superscript>13</Superscript>C-Octanoate Breath Test as a Surrogate Marker of Liver Damage in Animal Models

Background  

Octanoate (also known as sodium octanoate), a medium-chain fatty acid metabolized in the liver, is a potential substrate for non-invasive breath testing of hepatic mitochondrial β-oxidation.     

Use of prenatal care by Hispanic women after welfare reform

OBJECTIVE: The 1996 Personal Responsibility Work Opportunity Reconciliation Act (PRWORA, "welfare reform") changed immigrants' eligibility for publicly funded services such as Medicaid. However, implementation of the PRWORA varied by state. Florida implemented the eligibility restrictions, while California and New York preserved eligibility. Our objective was to compare the effect of state of residence and immigration status on use of prenatal care among Hispanic women in the period following the enactment of PRWORA. METHODS: In 1999-2001, we interviewed 3,242 postpartum Hispanic women in California, Florida, and New York. The dependent variable was use of prenatal care, dichotomized as adequate (initiated during the first trimester and > or = 6 visits, referent) or inadequate (initiated during the first trimester and < 6 prenatal visits or initiated after the first trimester). The primary independent variables were state of residence and maternal immigration status (U.S.-born citizens in New York, reference group). RESULTS: Thirteen percent of women were U.S.-born citizens, 8% were foreign-born citizens, 15% were documented immigrants, and 64% were undocumented immigrants. In Florida, women in all immigration subgroups were 2-4 times more likely to make inadequate use of prenatal care than U.S.-born citizens in New York. Documented immigrant women in New York were 90% more likely to make inadequate use of prenatal care than U.S.-born citizens in New York. CONCLUSION: Among Hispanic women in California, Florida, and New York, the state of residence, a measure of PRWORA policy changes, was associated with use of prenatal care. LEVEL OF EVIDENCE: II-2.     

Vulvovaginitis

The evaluation of vulvovaginitis, which is common in pediatric practice, depends on the pubertal development of the patient, keeping the possibility of sexual abuse in mind. Prepubescent girls are especially susceptible to vulvovaginitis because of anatomic and hormonal factors and because of their tendency to have poor local hygiene. If symptoms persist despite hygienic measures vaginal secretions should be investigated microbiologically and specific antimicrobial treatment prescribed accordingly. When the major complaint is of perineal pruritus, especially at night, empirical treatment with Mebendazole can be considered. In adolescents, who usually present with vaginal discharge, pruritus or dysuria, the pH of vaginal secretions should be tested and the secretions should be examined under the light microscope and sent for microbiological investigations. Physiologic leukorrhea is a common cause of vaginal discharge in adolescents. In the sexually active adolescent a complete pelvic examination with speculum should be performed including evaluation of endocervical specimen for sexually transmitted pathogens. Treatment is then directed at the specific cause. The diagnosis of one sexually transmitted disease necessitates investigation for others and treatment of the partner.