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PURPOSE To evaluate whether ethnicity affects the risk of full mutation expansion among females heterozygous for FMR1 premutation. METHODS Women who carry the FMR1 premutation alelle of Jewish origin who underwent fragile X prenatal diagnosis between 2011 and 2018 in two medical centers in Israel were included. The heterozygote women and fetuses were analyzed for the number of CGG repeats and AGG interruptions. RESULTS Seven hundred sixty-six subjects were included. Parental ethnicity was fully concordant in 592 cases (Jewish, Ashkenazi, and non-Ashkenazi). Ashkenazi compared with non-Ashkenazi heterozygotes have a significantly higher mean number of CGG repeats (68 ± 8.7, 64 ± 6.4 respectively, P = 0.03) and a lower mean number of AGG interruptions (0.89 ± 0.83, 1.60 ± 1.18 respectively, p = 0.0001). Overall, 56/198 (28.2%) fetuses of Ashkenazi heterozygotes had an expansion to a full mutation compared with 6/98 among the non-Ashkenazi (6.1%) (p = 0.001). Multivariate analysis demonstrated that, in addition to CGG repeats and AGG interruptions (which contributed 68.3% of variance), ethnicity is an independent risk factor for a full mutation expansion (odds ratio [OR] = 2.04, p

FMR1 premutation (55–200 CGG repeats) results in fragile X-associated primary ovarian insufficiency (FXPOI). We evaluated expression levels of folliculogenesis-related mediators, follicle-stimulating hormone (FSH) receptor and anti-Mullerian hormone (AMH), to gain insights into the mechanisms underlying the reduced ovarian function. Mural granulosa cells (MGCs) were collected from FMR1 premutation carriers and noncarriers undergoing IVF treatments. At baseline, MGCs of carriers demonstrated significantly higher mRNA expression levels of AMH (3.5 ± 2.2, n = 12 and 0.97 ± 0.5, n = 17, respectively; p = 0.0003) and FSH receptor (5.6 ± 2.8 and 2.7 ± 2.8, respectively; p = 0.02) and higher AMH protein expression on immunostaining. Accordingly, FMR1 premutation-transfected COV434 cells exhibited higher AMH protein expression than COV434 cells transfected with 20 CGG repeats. We conclude that FMR1 premutation may lead to dysregulation of AMH expression levels, probably due to a compensatory mechanism. Elucidating the pathophysiology of FXPOI may help in early detection of ovarian dysfunction and tailoring IVF treatments to FMR1 premutation carriers.

PURPOSE: To detect which factors influence decision-making among pregnant FMR1 premutation carriers regarding the preferred mode of genetic diagnosis: IVF-PGT-M (in vitro fertilization with preimplantation genetic testing for monogenic gene diseases), or CVS (chorionic villus sampling), or AC (amniocentesis) after spontaneous conception. METHODS: In Israel FMR1 premutation preconception genetic screening is offered, free of charge, to every woman in her reproductive years. FMR1 premutation carriers with ≥ 70 CGG repeats, or a history of FXS offspring, are offered IVF-PGT-M. This is a historical cohort study including all pregnant FMR1 premutation carriers who underwent prenatal diagnosis between the years 2011 and 2016 at a tertiary medical center. Data were collected from electronic charts and through phone interviews. RESULTS: One hundred seventy-five women with high-risk pregnancies who were offered IVF-PGT-M were evaluated. In 37 pregnancies (21%), the women decided to undergo IVF-PGT-M. Using the generalized estimating equations (GEE) statistical method including seven parameters, we found that previous termination of pregnancy due to FXS and advanced woman’s age were significantly associated with making the decision to undergo IVF-PGT-M. Previously failed IVF was the most significant parameter in a woman’s decision not to undergo IVF-PGT-M. CONCLUSION: The most dominant factor affecting the decision of FMR1 premutation carriers to choose spontaneous conception with prenatal diagnosis versus IVF-PGT-M is a previous experience of failed IVF treatments. Women whose IVF treatments failed in the past tended to try to conceive naturally and later, during the course of the pregnancy, perform CVS or AC. Conversely, women who previously experienced a termination of pregnancy (TOP) due to an affected fetus, and older women, preferred to undergo IVF-PGT-M procedures.

We aim to retrospectively evaluate the role of increasing the gonadotropin daily dose from 450 IU/day to 300 IU twice a day on IVF-ET outcome in poor responder patients. All consecutive women admitted to our IVF unit and underwent COH consisting of daily gonadotropin dose of 450 IU, followed by an IVF cycle using 300 IU twice a day, were included. Ovarian stimulation characteristics, number of oocytes retrieved, number of embryo transferred and pregnancy rate was assessed. Twenty-three patients undergoing both cycles were evaluated. While there was no between-group difference in the duration of COH, number of 2PN embryos, fertilization rate and number of embryos transferred, patients receiving daily gonadotropin 300 IU twice a day achieved a significantly higher peak estradiol levels (3350.39 ± 2364.26 vs. 2223.74 ± 1299.91

Fragile X syndrome (FXS) is the most prevalent known genetically inherited cause for autism and intellectual disability. Premutation state can cause several clinical disorders as well. We aimed to perform a nesting approach to acquire data with regard to first degree relatives of index fragile X cases at the largest child development center in Israel in order to map characteristics of Israeli FXS permutation women carriers. Seventy-nine women were referred due to a related fragile X syndrome patient, mainly an offspring or sibling. General information regarding demographics, ethnicity, and associated medical conditions were collected using interviews and structured questionnaires. Thirteen (17 %) of the women who were referred as "carrier" were proven to be actually full mutation. The mean years of education were 14 (±1.51, range 12-17). Twenty-one women (27 %) originated from Tunisia (mainly from the island of Djerba). Ten women (13 %) reported delivery of their affected offspring beyond 41 gestational weeks. Twenty-two percent of women with premutation reported symptoms consistent with learning difficulties, mainly dyscalculia, and 14 % reported ADHD symptoms. Awareness about clinical disorders of the carriers was existent only in 25 % of the patients. Increased awareness and knowledge dissemination concerning premutation symptomatology and associated medical conditions are warranted. We suggest a national registry to be installed in different countries in order to identify fragile X premutation carriers at increased risk for various medical complications.

Abnormalities in the X-linked FMR1 gene are associated with a constellation of disorders, which have broad and profound implications for the person first diagnosed, and extended family members of all ages. The rare and pleiotropic nature of the associated disorders, both common and not, place great burdens on (1) the affected families, (2) their care providers and clinicians, and (3) investigators striving to conduct research on the conditions. Fragile X syndrome, occurring more severely in males, is the leading genetic cause of intellectual disability. Fragile X associated tremor and ataxia syndrome (FXTAS) is a neurodegenerative disorder seen more often in older men. Fragile X associated primary ovarian insufficiency (FXPOI) is a chronic disorder characterized by oligo/amenorrhea and hypergonadotropic hypogonadism before age 40 years. There may be significant morbidity due to: (1) depression and anxiety related to the loss of reproductive hormones and infertility; (2) reduced bone mineral density; and (3) increased risk of cardiovascular disease related to estrogen deficiency. Here we report the case of a young woman who never established regular menses and yet experienced a 5-year diagnostic odyssey before establishing a diagnosis of FXPOI despite a known family history of fragile X syndrome and early menopause. Also, despite having clearly documented FXPOI the woman conceived spontaneously and delivered two healthy children. We review the pathophysiology and management of FXPOI. As a rare disease, the diagnosis of FXPOI presents special challenges. Connecting patients and community health providers with investigators who have the requisite knowledge and expertise about the FMR1 gene and FXPOI would facilitate both patient care and research. There is a need for an international natural history study on FXPOI. The effort should be coordinated by a global virtual center, which takes full advantage of mobile device communication systems.

STUDY QUESTION: What are the effects of thin ovarian grafts compared with grafts of the standard thickness on follicle loss post-transplantation? SUMMARY ANSWER: Transplantation of reduced-thickness ovarian grafts led to intense activation and 'burn-out' a short time after transplantation resulting in significant folllicle loss. WHAT IS KNOWN ALREADY: Transplantation of fresh and frozen-thawed ovarian tissue has been proved successful, but techniques vary and are not optimised, often resulting in significant follicular loss. Follicle loss is mostly related to the freezing-thawing process and to post-transplantation hypoxia. STUDY DESIGN, SIZE, DURATION: Bovine ovarian tissue strips (n = 55) were prepared in two groups of conventional-thickness strips (1-2 mm) or thin strips (0.5-0.9 mm). Fresh or frozen-thawed samples were xenotransplanted into sterilized immune-deficient mice (n = 49). Non-transplanted conventional size fresh samples were used as controls (n = 6). Grafts from all study groups were recovered after 7 days for analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Morphometric differential counting of follicle classes was performed by two observers. Immunohistochemistry was conducted for proliferation (Ki67), cortical fibrosis (Masson tri-chrome) and blood-vessel density (CD31). Results were expressed as the mean number of dormant or growing follicle (GF) type per section or total follicle counts per graft. Blood-vessel density was calculated per mm(2). P-values

Identification of non-small cell lung carcinoma (NSCLC) patients at high-risk for recurrence after complete resection would potentially direct surveillance frequency and administration of adjuvant treatments. Genetic profiling of tumors could provide clinicians with information regarding recurrence risk. Conflicting evidence exists regarding EGFR, KRAS, and TP53 mutations as prognostic for recurrence. We aimed to test such mutations for prognostic significance in a cohort of early-resected NSCLC specimens. Formalin-fixed paraffin-embedded stage I NSCLC specimens resected in our institute during 1988–2008 were sampled. DNA was extracted and a panel of common EGFR, KRAS, and TP53 mutations was tested using a mass-spectrometry-based technique. Clinical data were extracted from patients’ files. A total of 96 NSCLC stage I patients were included in this study. EGFR mutation frequency of 15.6 %, KRAS mutation frequency of 15.6 %, and a TP53 mutation frequency of 6.2 % were found. A nonsignificant trend for longer relapse-free survival (RFS) was seen for patients with an EGFR mutation, and a nonsignificant trend for worse RFS was found for patients with a KRAS mutation. EGFR mutation and KRAS mutation were not found to be prognostic for RFS in our cohort of early NSCLC. Larger cohorts and a broader genetic screen for mutations are required.

The brains of Long Evans shaker (les) rats, a model of dysmyelination, and their age- matched controls were studied by ex-vivo q-space diffusion imaging (QSI) and diffusion tensor imaging (DTI). The QSI and DTI indices were computed from the same acquisition. The les and the control brains were studied at different stages of maturation and disease progression. The mean displacement, the probability for zero displacement and kurtosis were computed from QSI data while the fractional anisotropy (FA) and the eigenvalues were computed from DTI. It was found that all QSI indices detect the les pathology, at all stages of maturation, while only some of the DTI indices could detect the les pathology. The QSI mean displacement was larger in the les group as compared with their age-matched controls while the probability for zero displacement and the kurtosis were both lower all indicating higher degree of restriction in the control brains. Since all the DTI eigenvalues were higher in the les brains as compared to controls, the less efficient DTI measure for discerning the les pathology was found to be the FA. Clearly, the most sensitive DTI parameter to the les pathology is λ3, i.e., the minimal diffusivity. Since the QSI and DTI data were obtained from the same acquisition, despite the somewhat higher SNR of the QSI data compared to the DTI data, it seems that the higher diagnostic capacity of the QSI data in this experimental model of dysmyelination, originates mainly from the higher diffusing weighting of the QSI data.

The main aim was to develop recommendations on eMental health interventions for the treatment of psychotic disorders. A systematic literature search on eMental health interventions was performed, and 24 articles about interventions in psychotic disorders were retrieved and systematically assessed for their quality. Studies were characterized by a large heterogeneity with regard to study type, sample sizes, interventions and outcome measures. Five graded recommendations were developed dealing with the feasibility of eMental health interventions, beneficial effects of psychoeducation, preliminary results of clinical efficacy, the need of moderation in peer support eMental health groups and the need to develop quality standards.

The JAK2V617F mutation has emerged in recent years as a diagnostic as well as treatment target in patients with polycythemia vera (PV). We analyzed JAK2V617F allele burden (JAK2(V617F)) in a Jewish population with PV. Results were correlated with disease symptoms and complications. Median JAK2(V617F) was 48% and 54% in patients of Ashkenazi and non-Ashkenazi origin, respectively (p =0.75). Higher JAK2(V617F) was seen in patients with imaging-proven splenomegaly (p =0.01). A correlation between JAK2(V617F) and the weekly hydoxyurea dose needed for disease control was found (p =0.043). In addition, a trend for higher allele burden in patients with longer disease duration (p =0.064) and those treated with cytoreductive drugs other than hydroxyurea (p =0.056) was noted. Higher JAK2(V617F) was seen in patients with transformation to myelofibosis (p =0.0001), but not in patients with vascular complications. JAK2(V617F) may assist in prognostic stratification of patients with PV.

Organophosphates are highly toxic substances, which cause severe brain damage. The hallmark of the brain injury is major convulsions. The goal of this study was to assess the spatial and temporal MR changes in the brain of paraoxon intoxicated rats. T2-weighted MRI and ¹H-MR-spectroscopy were conducted before intoxication, 3 h, 24 h, and 8 days postintoxication. T2 prolongation mainly in the thalami and cortex was evident as early as 3 h after intoxication (4-6% increase in T2 values, P 20% decrease, P 15%, P < 0.05). Animals who succumbed had extensive cortical edema, significant higher lactate levels and a significant decrease in NAA/creatine and NAA/choline levels compared to animals which survived the experiment. Organophosphates-induced brain damage is obvious on MR data already 3 h postintoxication. In vivo spectroscopic changes are more sensitive for assessing long-term injury than T2-weighted MR imaging. Early spectroscopic findings might be used as biomarkers for the severity of the intoxication and might predict early survival.

Purpose: To assess, by MR spectroscopy (MRS) and diffusion weighted imaging (DWI), the ability of electrical stimulation of the sphenopalatine ganglion (SPG) to augment stroke recovery in transient middle cerebral artery occluded (t-MCAO) rats, when treatment is started 18 6 2 h post-occlusion. Materials and Methods: 1 H-MRS imaging ( 1 H-MRSI) and DWI were used to evaluate ischemic brain tissue after SPG stimulation in rats subjected to 2 h of t-MCAO. Rats were examined by 1 H-MRSI, DWI, and behavioral tests at 16 6 2 h, 8 days, and 28 days post-MCAO. Results: N-Acetyl-aspartate (NAA) levels of the stimulated and control rats were the same 16 6 2 h post-MCAO (0.52 6 0.03, 0.54 6 0.03). At 28 days post-occlusion, NAA levels were significantly higher in the treated group (0.60 6 0.04) compared with those of the untreated animals (0.50 6 0.04; P < 0.05). This effect was more pronounced for regions with low NAA values (0.16 6 0.03) that changed to 0.32 6 0.03 (P ¼ 0.04) for the treated group and to 0.10 6 0.03 (P ¼ 0.20) for the controls. DWI data showed better ischemic tissue condition for the treated rats, but the measured parameters showed only a trend of improvement. The MR results were corroborated by behavioral examinations. Conclusion: Our findings suggest that SPG stimulation may ameliorate MR tissue characteristics following t-MCAO even if treatment is started 18 h post-occlusion.

Quinolinic acid (QA) induced striatal lesion is an important model for excitotoxicity that is also used for efficacy studies. To date, the morphological and spectroscopic indices of this model have not been studied longitudinally by MRI; therefore the objectives of this study were aimed at following the lesion progression and changes in N-acetyl aspartate (NAA) as viewed by MRI and MRSI, respectively, in-vivo over a period of 49 days. We found that the affected areas exhibited both high and low apparent diffusion coefficients (ADC) even 49 days post QA injection in three of the six tested animals. MRI-guided histological analysis correlated areas characterized by high ADCs on day 49 with cellular loss, while areas characterized by lower ADCs were correlated with macrophage infiltration (CD68 positive stain). Our MRSI study revealed an initial reduction of NAA levels in the lesioned striatum, which significantly recovered with time, although not to control levels. Total-striatum normalized NAA levels recovered from 0.67 +/- 0.15 (of the contralateral row) on day 1 to 0.90 +/- 0.12 on day 49. Our findings suggest that NAA should be considered as a marker for neuronal dysfunction, in addition to neuronal viability. Some behavioral indices could be correlated to permanent neuronal damage while others demonstrated a spontaneous recovery parallel to the NAA recovery. Our findings may have implications in efficacy-oriented studies performed on the QA model.

Purpose: To investigate the neuroprotective effect of brimonidine following induction of ischaemic optic neuropathy in rodents (rAION). Methods: Mice were treated with an intraperitoneal injection of brimonidine 48, 24 or 0 h before rAION induction or eye drops for 5 days after rAION induction. Retinal ganglion cell (RGC) loss and expression of genes involved in the angiogenesis (vascular endothelial growth factor [VEGF], pigment epithelium-derived factor [PEDF], The epidermal growth factor homology domains-2 [Tie-2]), ischaemia (haem oxygense-1 [HO-1], hypoxia-inducible factor 1α[HIF-1α], endothelial nitric oxide synthase [eNOS]) and oxidative stress (superoxide dismutase-1 [SOD-1], glutathione peroxidase-1 [GPX-1]) response to ischaemic damage were compared with sham or rAION-untreated mice. Results: No RGC loss was detected in the brimonidine-treated mice. Effect of post-rAION eye drops: day 1 – no decrease in retinal mRNA levels of angiogenesis-related genes, increase in ischaemia- and oxidative stress-related genes except HIF-1α; day 3 – baseline or higher levels of oxidative and ischaemia-related genes except HIF-1α, increase in VEGF, decrease in PEDF; day 21 – no change in angiogenesis-related genes. Effect of pre-rAION injection: baseline levels of angiogenesis-related genes with all injection schedules; increase in ischaemia-related genes with 48-h and 0-h pretreatment; decrease in HO-1 and eNOS with 24-h pretreatment; increase in oxidative-related genes except GPX-1. In optic nerve tissue, HO-1, HIF-1α and SOD-1 decreased on day 1 after topical administration and were still below baseline on day 3. Conclusions: The increase in HO-1 associated with rAION is mitigated with brimonidine treatment, especially when administered intraperitoneally. Topical brimonidine apparently reduces VEGF, Tie-2, HIF-1α and GPX-1 expression on day 21. These results agree with published data and may have therapeutic implications for patients diagnosed with AION in the acute phase.

Stem cell-based treatment is a promising frontier for neurodegenerative diseases. We propose a novel protocol for inducing the differentiation of rat mesenchymal stem cells (MSCs) toward neurotrophic factor (NTF)-secreting cells as a possible neuroprotective agent. One of the major caveats of stem cell transplantation is their fate post-transplantation. To test the viability of the cells, we tracked the transplanted cells in vivo by magnetic resonance imaging (MRI) scans and validated the results by histology. MSCs went through a two-step medium-based differentiation protocol, followed by in vitro characterization using immunocytochemistry and immunoblotting analysis of the cell media. We examined the migratory properties of the cells in the quinolinic acid (QA)-induced striatal lesion model for Huntington's disease. The induced cells were labeled and transplanted posterior to the lesion. Rats underwent serial MRI scans to detect cell migration in vivo. On the 19th day, animals were sacrificed, and their brains were removed for immunostaining. Rat MSCs postinduction exhibited both neuronal and astrocyte markers, as well as production and secretion of NTFs. High-resolution two-dimensional and three-dimensional magnetic resonance images revealed that the cells migrated along a distinct route toward the lesion. The in vivo MRI results were validated by the histological study, which demonstrated that phagocytosis had only partially occurred and that MRI could correctly depict the status of the migrating cells. The results show that these cells migrated toward a QA lesion and therefore survived for 19 days post-transplantation. This gives hope for future research harnessing these cells for treating neurodegenerative diseases. Disclosure of potential conflicts of interest is found at the end of this article.

JAK2 V617F mutation is found in a high proportion of MPD patients. We developed a quantitative assay for the detection of the JAK2 mutation and demonstrated its clinical utility in MPD patients who underwent SCT. Sixty percent of the patients were JAK2 V617F positive prior to the SCT (mean mutation levels 74%, range 16-98%). After the procedure, the mutation levels progressively decreased and were in correlation with the donor-recipient chimerism status (r=0.97, p

Alzheimer's disease (AD) and Vascular Dementia (VaD) are the most common types of dementia and are progressive diseases affecting millions of people. Despite the high sensitivity of MRI to neurological disorders it has not thus far been found to be specific for the detection of either of these pathologies. In the present study high b-value q-space diffusion-weighted MRI (DWI) was applied to VaD and AD. Controls (N=4), VaD patients (N=8) and AD patients (N=6) were scanned with high b-value DWI, which emphasizes the water component which exhibits restricted diffusion. VaD patients were found to present major WM loss while, in AD, the major pathology found was GM changes, as expected. Also, WM changes in VaD and AD were of a different pattern, more specific to frontal and temporal areas in AD and more widespread in VaD. This pattern of WM changes may be utilized as a diagnosis criterion. Conventional diffusion tensor imaging did not show significant changes between either of the groups and controls. These results demonstrate the potential of high b-value DWI in the diagnosis of dementia.

The aim of this study was to evaluate whether long noncoding RNA accumulation play a role in the pathophysiology of fragile X-associated premature ovarian insufficiency (FXPOI). The study population consisted of 22 consecutive fragile X mental retardation 1 (FMR1) premutation carriers (CGGn 55-199 repeats) undergoing in vitro fertilization and pre-implantation genetic diagnosis (IVF-PGD) treatment. The control group consists of 11 patients, with

Importance The risk for herpes zoster (HZ) in patients with psoriasis treated with biologic medications or other systemic treatments has been given little attention to date. Objective To describe the risk for HZ in patients with psoriasis and its relation to treatment. Design, Setting, and Participants A cohort study was performed using the administrative database of Clalit Health Services, the largest public health care provider organization in Israel, in the setting of general community clinics, primary care and referral centers, and ambulatory and hospitalized care. We extracted information for all patients who received a psoriasis diagnosis from January 2002 to June 2013. Follow-up was conducted until the end of July 2013. The study included 95 941 patients with psoriasis in the analysis, with 522 616 person-years of follow-up. Incidence of HZ events was calculated for each systemic antipsoriatic medication provided, during a follow-up period of 11 years and 7 months. We used a generalized estimating equation Poisson regression model to examine the effect of each systemic treatment for psoriasis on HZ incidence, adjusting for age, sex, psoriasis severity, Charlson comorbidity index, steroid treatment, and socioeconomic status. Main Outcomes and Measures Incidence of HZ associated with systemic therapies. Results In a multivariate analysis, it was observed that treatment with phototherapy (rate ratio [RR], 1.09 [95% CI, 0.62-1.93]; P = .99), methotrexate (RR, 0.98 [95% CI, 0.78-1.23]; P = .83), cyclosporine (RR, 1.16 [95% CI, 0.48-2.80]; P = .49), and biologic medications as a single agent (RR, 2.67 [95% CI, 0.69-10.3]; P = .14) was not associated with HZ. The use of combination treatment with biologic medications and methotrexate was significantly associated with an increased incidence of HZ (RR, 1.66 [95% CI, 1.08-2.57]; P = .02). The use of acitritin was associated with decreased incidence of HZ (RR, 0.69 [95% CI, 0.49-0.97]; P = .004). Conclusions and Relevance Physicians may need to consider offering an HZ preventive vaccine to patients receiving combination treatment with biologic medications and methotrexate, particularly if they have additional risk factors for HZ.

CYP2C9 and VKORC1 genetic variants are associated with low and intermediate warfarin dose requirements, but markers of high doses are less well characterized. We analyzed the VKORC1 coding sequence and known CYP2C9 and VKORC1 polymorphisms in 15 selected warfarin-resistant (dose, 80 to 185 mg/wk) and 8 warfarin-sensitive patients (7 to 13 mg/wk) and 99 unselected controls (8 to 105 mg/wk). We identified a coding VKORC1 Asp36Tyr polymorphism in 7 of 15 resistant compared with 0 of 8 sensitive patients (P = .026) Carriers of Asp36Tyr in the control group (8 of 99) required significantly higher warfarin doses of 80.9 ± 10.1 mg/wk compared with 42.7 ± 7.5 mg/wk in noncarriers (F = 9.79, P = .002). Asp36Tyr was significantly associated with doses of more than 70 mg/wk (odds ratio, 13.0; 95% confidence limit, 1.3 to 124.2), while doses of 20 to 70 mg/wk were associated with Asp36Tyr (partial r2 = .11; P = .004), CYP2C9*2 and *3 (r2 = .08; P = .01), and VKORC1*2 and *3 markers (r2 = .05; P = .05). All Asp36Tyr carriers also had VKORC1*1 tag–single nucleotide polymorphisms (tag-SNPs) indicating a new haplotype. Asp36Tyr was common in Jewish ethnic groups of Ethiopian (15%) and Ashkenazi (4%) origin. We suggest that Asp36Tyr is a new marker of the high end of the warfarin dosing range.

Experimental allergic encephalomyelitis (EAE) is the primary experimental model of multiple sclerosis (MS), which involves both inflammation and demyelination and is known to be species-dependent. Spinal cord abnormalities were found in more than 80% of postmortem specimens of MS patients. In the present study, T1, T2 and high b-value q-space diffusion-weighted magnetic resonance imaging (MRI) were used, for the first time, to characterize the EAE model in excised swine spinal cords. The MR images were compared with histological staining and clinical scoring. Although all spinal cords were excised from swine with severe or very severe (clinical score between 3 to 5 on a scale of 5) motor impairments, T1- and T2-weighted MRI revealed white matter (WM) abnormalities in only five of the ten EAE diseased spinal cords studied, while high b-value q-space diffusion weighted MRI (q-space DWI) detected WM abnormalities in all diseased spinal cords studied. Interestingly, high b-value q-space DWI was able to detect abnormalities in the normal appearing white matter (NAWM) even in spinal cords where no plaques were identified by the T1- and T2-weighted MR images. Good anatomical correlation was observed between the high b-value q-space MR images and histology. The extent of DWI abnormalities paralleled the clinical scoring and correlated with histology. In addition, areas classified as NAWM by the T1- and T2-weighted MR images that showed abnormalities in the q-space DWI were also found to have abnormal histology. This improved detection level of the EAE model by high b-value q-space DWI over conventional T1-, and T2-weighted MRI is briefly discussed.

Papillary thyroid carcinoma may encompass a mixed group of neoplasms where divergence in clinical behavior may reflect distinct genetic alterations. For example, young patients with papillary thyroid carcinoma have a better prognosis than affected adults, and their carcinomas are much more likely to harbor chromosomal rearrangements involving the RET proto-oncogene. Mutational activation of the BRAF oncogene has recently been identified as the most common genetic alteration in papillary thyroid carcinoma, but little is known about its frequency as a function of patient age. We tested 20 papillary thyroid carcinomas from young patients ranging from 10 to 17 years of age for the thymine (T) --adenine (A) missense mutation at nucleotide 1796 in the BRAF gene using a newly developed assay that employs a novel primer extension method (Mutector assay). The prevalence of BRAF mutation was compared with a larger group of papillary thyroid carcinomas from previously tested adult patients (20 years). BRAF mutations were not common in papillary thyroid carcinomas from young patients compared to their counterparts in adults (20 vs 77%; OR=13.3, 95% confidence interval (CI)=3.4-56.5; P0.0001), but they become increasingly prevalent with advancing patient age (OR as a function of age at 10-year intervals=1.80 CI=1.33-2.44; P0.001). Unlike papillary thyroid carcinomas that arise in adults, mutational activation of BRAF is not a major genetic alteration in papillary thyroid carcinomas that arise in young patients. The increasing frequency of BRAF mutations as a function of age could help account for the well documented but poorly understood observation that age is a relevant prognostic indicator for patients with papillary thyroid carcinoma.

Cholinergic imbalances occur after traumatic effects and in the initial stages of neurodegenerative diseases, but their long-lasting effects remained largely unexplained. To address this, we used TgS transgenic mice constitutively overexpressing synaptic acetylcholinesterase (AChE-S) and presenting a complex phenotype of progressive neurodeterioration. T1- and T2-weighted magnetic resonance (MR) brain images appeared similar. However, diffusion-weighted MRI showed decreased baseline water apparent diffusion coefficient in the brains of TgS animals. Furthermore, contrast-enhanced MRI after gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) injection demonstrated slower recovery of normal signals in the TgS brains than with controls. Perfusion MR imaging and difference T1 maps calculated from pre- postcontrast T1-weighted MR images indicated accumulation of more Gd-DTPA molecules in the TgS brains than in the parent strain, reflecting impaired blood-brain barrier (BBB) functioning in these transgenic mice. To explore the molecular mechanism(s) underlying these global phenotypes, we performed microarray analysis in the stress-controlling prefrontal cortex of TgS vs. strain-matched wild-type animals. Profound overexpression of numerous ion channels, transporters, and adhesion genes was confirmed by real time RT-PCR tests. Immunohistochemical and immunoblot analyses revealed corresponding increases in the level and cellular distributions of the chloride channel CLCN3 and the water channel AQP4, both of which contribute to BBB maintenance. Our study attributes to balanced cholinergic neurotransmission, a central role in the brain's maintenance of water diffusion and ion transport, and indicates that chronic impairments in this maintenance facilitate neurodeterioration through interference with BBB function.

To investigate the role of inflammation in acute retinal artery occlusion (RAO).Levels of interleukin (IL)-6, IL-8, and tumor necrosis factor alpha (TNF-alpha) were measured in serum (n = 14) and aqueous humor (AqH) (n = 8) samples from patients with RAO. Findings were compared with 24 age- and disease-matched patients, 10 healthy subjects (serum), and 16 patients undergoing cataract surgery (AqH).Patients who arrived early (within 4-6 hours of occlusion) had higher serum IL-8 and IL-6 levels than controls; the IL-6 level in the AqH was lower than that of controls, while the IL-8 level was higher. In seven patients for whom both serum and AqH samples were available, serum IL-6 levels were higher than their corresponding AqH levels in most patients arriving within 10 hours of occlusion, and AqH IL-8 levels were higher than the corresponding serum levels in all but one. TNF-alpha levels were consistently higher in the serum than in the AqH at all time points.Serum IL-8 and IL-6 and AqH IL-8 are elevated immediately following acute RAO. The early local suppression of IL-6 may be related to ocular immune mechanisms.

Objective . Our recent study determined the possible effects and incidence of BRCA1 and BRCA2 germline mutations in uterine serous papillary carcinoma (USPC). The purpose of this study was to determine the incidence of these mutations in an enlarged series of USPC. Methods . We screened DNA from 27 women with USPC for BRCA1 and BRCA2 germline mutations common in the Jewish population ( BRCA1 -185delAG and 5382 insC, BRCA2 -6174delT). In women with germline mutations, tumor DNA was screened for loss of heterozygosity (LOH) at the appropriate loci. Results . Women (20) were of Jewish Ashkenazi origin and seven were non-Ashkenazi. Four of 20 (20%) Ashkenazi women were carriers of germline mutations: three 185delAG mutation and one 5382insC mutation. All carriers had strong family histories of breast–ovarian carcinoma. Seven out of 20 (35%) women had been diagnosed for breast carcinoma before diagnosis of USPC. Family histories of 12 women (60%) showed at least one first-degree relative with breast, ovarian, or colon carcinoma. Loss of heterozygosity analysis found a loss of the wild-type BRCA1 allele in three of the four primary uterine tumors that were examined. Conclusions . Our findings further support our previous published data suggesting a high incidence of BRCA carriers among USPC Ashkenazi Jewish patients. The loss of heterozygosity in the tumor tissue of carriers coupled with the high frequency of patient and family history of breast and ovarian malignancies suggest that USPC might be part of the manifestation of familial breast–ovarian cancer in Ashkenazi Jewish patients.

Despite the many studies of the middle cerebral artery occlusion (MCAO) model, efficient therapy for stroke is still lacking, emphasizing the need for further development and characterization of experimental stroke models. In the present study, the rather unexplored multifocal microsphere-induced stroke model in rats was characterized by multiparametric MRI. We induced microembolic infarction in a group of Sprague-Dawley rats by injecting a dose of about 1000 50-m polyethylene microspheres intracranially from the external carotid artery. Diffusion-, perfusion-, and T2-weighted MRI were used to evaluate the infarct development during and following the first 3 hr after microsphere injection (N 20). The animals were also imaged at 12-hr (N 8), 24-hr (N 17), and 48-hr (N 5) time points. After the final imaging time point, the brains were removed and sectioned into 2-mm-thick slices, and infarct volumes were measured by 2,3,4-triphenyltetrazolium chloride (TTC) staining. From calculated apparent diffusion coefficient (ADC) maps, a volume of reduced ADC appeared 0.5–1.0 hr postinjection, and by the 3-hr time point the volume of ADC reduction had increased to a size of 5% 1% (mean SEM) of the brain hemisphere. The lesion volume increased significantly (P < 0.01) to 16% 2% of the hemisphere volume at the 12-hr time point, while at 24 hr the lesion (15% 2% of the hemisphere) was also significantly larger (P < 0.001) than at 3 hr. The perfusion deficit resulting from the microsphere injection was immediate, going from a cerebral blood flow index (CBFi )o f 74% 3% at the time of microsphere injection to 68% 2% of the contralateral mean at 3 hr (P < 0.05), to 55% 4% of the contralateral values at 12 hr (P < 0.05), and to 57% 2% of the contralateral mean at 24 hr (P < 0.001). The lesion development in the microsphere-induced stroke model was found to be slower than in the MCAO model, and continued up to the 24 – 48-hr time point. Magn Reson Med 51:1232–1238, 2004.

Hypertension is one of the major risk factors of stroke and vascular dementia (VaD). We used stroke prone spontaneous hypertensive rats (SPSHRs) as a model for neuronal degeneration frequently occurring in humans with vascular disease. Recently, high b value q-space diffusion-weighted imaging (DWI) was shown to be very sensitive to the pathophysiological state of the white matter. We studied the spinal cords of SPSHR rats ex vivo after the appearance of motor impairments using diffusion anisotropy and q-space diffusion imaging (measured at a high b value of up to 1 × 105 s/mm2). The diffusion anisotropy images computed from low b value data set (bmax approximately 2500 s/mm2) showed a small but statistically significant decrease (approximately 12%, P < 0.05) in the diffusion anisotropy in the spinal cords of the SPSHR group as compared to control rats. However, more significant changes were found in the high b value q-space diffusion images. The q-space displacement values in the white matter of the SPSHR group were found to be higher by more than 70% (P < 0.002) than that of the control group. These observations concurred with electron microscopy (EM) that showed significant demyelination in the spinal cords of the SPSHR group. These results seem to indicate that high b value q-space DWI might be a sensitive method for following demyelination and axonal loss associated with vascular insults.

High b value diffusion weighted magnetic resonance imaging (high-b DWI) was used to characterize white matter changes in the brain of patients with vascular dementia (VaD). Hyperintense white matter areas detected by T2-weighted magnetic resonance imaging (MRI) represent lesions, also termed leukoaraiosis that are very common in VaD as well as in other types of dementia. Therefore, the role of white matter changes in the cognitive and memory decline that occurs in VaD patients is still under debate. High-b DWI, analyzed using the q-space approach, is a more sensitive MRI method for detection of white matter changes. High-b DWI revealed massive white matter loss in VaD patients that surpassed the boundaries of T2 hyperintensities. This technique, therefore, might serve as a better indication for the extensive nerve fiber loss in the white matter that is caused by vascular disease.

AimTo assess the role of mRNA accumulation in granulosa cells as the cause of low ovarian response among FMR1 premutation carriers undergoing pre-implantation genetic diagnosis (PGD).DesignCase control study in an academic IVF unit. Twenty-one consecutive FMR1 premutation carriers and 15 control women were included. After oocyte retrieval the granulosa cells mRNA levels of FMR1 was measured using RT-PCR.ResultsIn FMR1 premutation carriers, there was a significant non-linear association between the number of CGG repeats and the number of retrieved oocytes (pConclusionWe suggest that there is a no-linear association between the number of CGG repeats and ovarian function, resulting from an increased granulosa cells FMR1 mRNA accumulation in FMR1 carriers in the mid-range (80-120 repeats).

Background and Objectives: Peritoneal papillary serous carcinoma (PPSC) is histologically and clinically similar to stage III–IV ovarian papillary serous carcinoma (OPSC). The purpose of this study was to investigate the clinical findings, treatment, and outcome of PPSC patients compared with stage III–IV OPSC patients. Methods Data from the files of 15 PPSC patients and 52 stage III–IV OPSC patients who were managed at the Soroka Medical Center between January 1991 and December 1997 were evaluated. Results With regard to patients' characteristics, presenting signs and symptoms, type and extent of surgery, tumor response to first-line chemotherapy, recurrence-free interval, recurrence site, tumor response to second-line chemotherapy, and serum CA-125 levels, no significant differences were observed between the PPSC patients and the stage III–IV OPSC controls. The prevailing presenting symptoms were abdominal mass and ascites. The mainstay of treatment was debulking surgery followed by adjuvant platinum-containing chemotherapy. The objective response rate to first-line chemotherapy was 80%. The actuarial 5-year survival rate for the PPSC patients and stage III–IV OPSC patients was 52.0% and 20.5%, respectively (0.05 < P < 0.1). Conclusions The clinical and surgical characteristics of patients with PPSC are similar to those of patients with stage III–IV OPSC. When treatment strategies for stage III–IV OPSC are applied to PPSC, the survival of PPSC patients may be similar or even better than that of stage III–IV OPSC patients. J. Surg. Oncol. 1998;68:173–178. © 1998 Wiley-Liss, Inc.

Uterine papillary serous carcinoma (UPSC) is an uncommon highly malignant variant of endometrial carcinoma that histologically and clinically resembles ovarian papillary serous carcinoma. The purpose of this study was to present the conjoined experience of two regional hospitals in the south of Israel (Soroka Medical Center, Beer-Sheva and Kaplan Hospital, Rehovot) of handling this tumour.Data from the files of 19 patients with UPSC who were managed at these hospitals between July 1991 and June 1997 were evaluated.The three-year survival rate was 57.3% overall; 83.3% for Stage I and 21.2% for Stages II, III, and IV combined (P0.02). Eighteen patients had primary surgery which included total abdominal hysterectomy and bilateral salpingo-oophorectomy and 15 (83.3%) of them received postoperative adjuvant therapy which included radiotherapy and/or systemic chemotherapy.The prognosis of patients with UPSC is worse than that of patients with other forms of endometrial carcinoma. Primary surgery comprised of total abdominal hysterectomy, bilateral salpingo-oophorectomy and staging is the mainstay of treatment. The type of postoperative treatment is not consistent. By and large, adjuvant pelvic radiotherapy is usually given in early-stage disease and adjuvant systemic chemotherapy is usually prescribed in advanced-stage disease.

Diffusion- and T2-weighted MRI were used to evaluate changes in brain water characteristics following closed-head injury in rats. Images were collected within the first 2 h and at 24 h and 7 days following the traumatic event and then compared with histology. The ratios between the apparent diffusion coefficients (ADCs) of the traumatized tissues and normal brain tissues were significantly different from unity and were found to be 0.79 +/- 0.25 (p0.01), 0.49 +/- 0.33 (p0.0002), and 3.47 +/- 1.36 (p10(-6)) at 1-2 h, 24 h, and 1 week after the trauma, respectively. In severe trauma, areas of hyperintensity which were not apparent on the T2-weighted images could be detected on the diffusion-weighted images within 1-2 h after the trauma. At 24 h following the traumatic event, large areas of hyperintensity are observed in both types of images. One week following the trauma, the ADCs of the traumatized tissues (1.84 +/- 0.69 x 10(-5) cm2/s) are much larger than those of normal brain (0.57 +/- 0.19 x 10(-5) cm2/s) and approach the value of free water. At 7 days, the areas of hyperintensity in the T2-weighted images seem to underestimate the injured areas found by histology. At this time point a good correlation is obtained between the areas of hypointensity observed on the diffusion-weighted images and the infarct areas obtained by histology (r = 0.88).

Background Uterine sarcomas are rare, characterized by rapid clinical progression and poor prognosis, and their management has been a challenge. The purpose of this study was to investigate the clinical and histologic findings, treatment, and outcome of patients with uterine sarcoma in the south of Israel. Methods Data from the files of 36 patients with uterine sarcoma who were managed at the Soroka Medical Center between January 1961 and December 1994 were evaluated. Results The 5-year survival rate was 32% overall; 63% for 9 patients with endometrial stromal sarcoma (ESS), 30% for 14 patients with mixed mesodermal sarcoma (MMS) and 18% for 13 patients with leiomyosarcoma (LMS); 41% for 22 patients with Stage I and 19% for 14 patients with Stages II, III, and IV. Only the difference in the 5-year survival rate between ESS and LMS was statistically significant (P < 0.05). Eleven patients (30.6%) were treated with surgery alone, 4 (11.1%) with surgery followed by pelvic radiotherapy, 11 (30.6%) with surgery followed by chemotherapy, 8 (22.2%) with surgery followed by pelvic radiotherapy and chemotherapy, one (2.8%) with chemotherapy alone, and one (2.8%) had no treatment. Conclusions Uterine sarcomas are aggressive tumors with a poor prognosis. The treatment is surgery generally followed by adjuvant pelvic radiotherapy and/or systemic chemotherapy. J. Surg. Oncol. 64:55–62 © 1997 Wiley-Liss, Inc.

Background. Recently, a high incidence of BRCA1 cancer predisposing mutation was described among patients with Uterine Serous Papillary Carcinoma (USPC). A BRCA2 germline mutation in a USPC patient has never been reported. Case. A 65-year-old Ashkenazi Jewish woman was diagnosed with USPC Stage III A. The patient family history included a mother with ovarian carcinoma, a maternal aunt who had breast carcinoma that was diagnosed at an early age, an additional maternal aunt who suffered from gastric carcinoma, and the patient's sister who had duodenal carcinoma. The patient was found to be a carrier of the germline BRCA2 cancer predisposing mutation (6174delT). Conclusions. We report the first case of a BRCA2 mutation in a USPC patient. A strong family history of breast and ovarian cancer with the presence of the BRCA2 germline mutation is an additional hint for the possible association between BRCA cancer predisposing mutations and USPC.

Preoperative radio-chemotherapy (RCT) may play an important role in decreasing local recurrence and possibly improving survival for patients with advanced rectal carcinoma.Between 1995 and 1998 we treated 30 patients (pts) (median age 61.5 years) with advanced low rectal cancer. Radiotherapy was administered using a 10-MV linear accelerator delivering a total dose of 45 Gy to the pelvis over 5 weeks. 5-FU (500 mg/m2/d i.v.) was given concomitantly on days 1-3 and 29-31. Surgery was performed 2-4 weeks after RCT and included abdomino-perineal resection (APR) in 15 pts, anterior resection in 11 pts, transanal resection in 1 pt, and explorative laparotomy in 1 pt; 2 pts refused surgery.There were no serious toxicities associated with RCT. Mild to moderate transient radiation dermatitis was noted in 3 pts, and grade II diarrhea in 4 pts. Postoperative pathologic staging was as follows: no tumor found (CR): 4 pts, MAC B1 (T2N0M0): 5 pts, MAC B2 (T3N0M0): 17 pts, B3 (vaginal involvement): 1 pt, MAC C2 (T3N1M0): 2 pts, and MAC D: 1 pt. Necrosis and/or fibrosis was noted as a prominent histopathologic feature.Preoperative RCT in this series of 30 pts with advanced rectal cancer was well tolerated and associated with a high response rate (13% CR, 17% PR, 57% NC). 5-year overall survival was 70%, and 8-year survival was 58%.

Endometriosis is associated with an increased risk of ovarian cancer. Few studies have also shown increased risk of breast cancer. BRCA1/2 mutations are linked to an increased risk of breast and ovarian cancers but their relation to endometriosis is unknown. The objective of this study was to examine the mutation rate of BRCA1/2 among women with surgically treated ovarian endometriosis. We collected 126 specimens from Jewish Ashkenazi women with endometriotic (76) and control non-endometriotic (50) ovarian cysts, reviewed the pathological diagnoses and extracted DNA from all samples. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), samples were examined for the founder germline mutations of BRCA1/2, most common among Ashkenazi Jews. The rate of mutations in each group was calculated and compared. BRCA1/2 mutation rate was 1/76 (1.3%) in the endometriotic cyst study group and 1/50 (2%) in the control non-endometriotic cysts, showing no statistically significant difference between the groups (p=0.84). BRCA1/2 mutation rate was similar to the previously reported rate among Jewish Ashkenazi women. BRCA1/2 mutation rates in patients with endometriotic ovarian cysts and with non-endometriotic ovarian cysts are similar. A larger cohort is required to completely exclude the possibility of an association between BRCA1/2 mutations and surgically treated endometriosis.

In a study of 37 patients diagnosed with cervical adenocarcinoma between 1961 and 1994, clinical and pathologic findings were evaluated. Of the 37 patients, 27 (73%) had a pure adenocarcinoma, five (13.5%) had a collision tumor and five (13.5%) had an adenosquamous carcinoma. Twenty-six patients (70.3%) were diagnosed in Stage I, and 11 (29.7%) patients in Stage II, III, and IV. Two patients (5.4%) were treated with simple hysterectomy alone, nine (24.3%) with simple hysterectomy followed by radiotherapy, eight (21.6%) with radical hysterectomy alone, five (13.5%) with radical hysterectomy followed by radiotherapy, nine (24.3%) with radiotherapy alone, one (2.7%) with radiotherapy followed by simple hysterectomy, and three (8.1%) received no treatment. The actuarial 5-year survival rate was 69%. It is suggested that for patients with small early-stage disease, radical hysterectomy should be primary treatment and postoperative adjuvant radiotherapy would be advocated if high-risk features are histologically demonstrated. For all other patients, radiotherapy should be primary treatment.

Our objective was to determine the pregnancy outcome in women who underwent a Shirodkar cerclage following a failed McDonald procedure in previous pregnancy. The study included 62 women who underwent an elective Shirodkar procedure between week 9 and week 15 of their singleton pregnancies. They had all failed to complete 34 weeks of gestation in their previous pregnancy despite the use of a McDonald cerclage. Complications observed included premature contractions in 18 patients (29.0%), preterm premature rupture of the membranes (PROM) in 7 (11.3%), vaginal bleeding in 6 (9.7%), chorioamnionitis in 2 (3.2%), cervical laceration in 1 (1.6%), and a single case (1.6%) of rupture of the uterus. Spontaneous abortion ( 37 weeks gestation) in 41 (66.1%) of the women. The fetal survival rate was 88.7% (55 viable newborns). I...

Diffusion MRI is extensively used to study brain microarchitecture and pathologies, and water diffusion appears highly anisotropic in the white matter (WM) of the spinal cord (SC). Despite these facts, the use of diffusion MRI to study the SC, which has increased in recent years, is much less common than that in the brain. In the present review, after a brief outline of early studies of diffusion MRI (DWI) and diffusion tensor MRI (DTI) of the SC, we provide a short survey on DTI and on diffusion MRI methods beyond the tensor that have been used to study SC microstructure and pathologies. After introducing the porous view of WM and describing the q-space approach and q-space diffusion MRI (QSI), we describe other methodologies that can be applied to study the SC. Selected applications of the use of DTI, QSI, and other more advanced diffusion MRI methods to study SC microstructure and pathologies are presented, with some emphasis on the use of less conventional diffusion methodologies. Because of length constraints, we concentrate on structural studies and on a few selected pathologies. Examples of the use of diffusion MRI to study dysmyelination, demyelination as in experimental autoimmune encephalomyelitis and multiple sclerosis, amyotrophic lateral sclerosis, and traumatic SC injury are presented. We conclude with a brief summary and a discussion of challenges and future directions for diffusion MRI of the SC. Copyright © 2016 John Wiley & Sons, Ltd.

In a study of 20 patients diagnosed with malignant ovarian germ cell tumors between 1961 and 1993, clinical and pathologic findings were evaluated. Of the 20 patients, seven (35%) had dysgerminoma, two (10%) endodermal sinus tumor, three (15%) malignant teratoma, one (5%) malignant struma ovarii, one (5%) primary ovarian carcinoid, two (10%) benign teratoma with malignant transformation, and four (20%) combination germ cell tumor. Twelve patients (60%) had stage IA, five (25%) stage IC, and three (15%) stage IIIC. Twelve patients (60%) underwent conservative surgery and eight (40%) had at least bilateral salpingo-oophorectomy. At follow-up, 18 patients (90%) were alive free of disease, one (5%) had died of disease, and one (5%) had died of intercurrent disease. The actuarial 5-year survival rate was 93.3%. It is concluded that for young women who wish to preserve child-bearing capacity, regardless of the stage of the tumor, fertility-preserving surgery with complete surgical staging followed, if necessary by cisplatin-based combination chemotherapy is an appropriate and definitive treatment in the absence of involvement of the contralateral ovary and uterus. For patients in whom child-bearing capacity is not an issue, surgery should include total abdominal hysterectomy and bilateral salpingo-oophorectomy with complete staging, followed if necessary by chemotherapy.

The BRAF gene has been found to be activated by mutation in human cancers, predominantly in malignant melanoma. We tested 476 primary tumors, including 214 lung, 126 head and neck, 54 thyroid, 27 bladder, 38 cervical, and 17 prostate cancers, for the BRAF T1796A mutation by polymerase chain reaction (PCR)-restriction enzyme analysis of BRAF exon 15. In 24 (69%) of the 35 papillary thyroid carcinomas examined, we found a missense thymine (T)-->adenine (A) transversion at nucleotide 1796 in the BRAF gene (T1796A). The T1796A mutation was detected in four lung cancers and in six head and neck cancers but not in bladder, cervical, or prostate cancers. Our data suggest that activating BRAF mutations may be an important event in the development of papillary thyroid cancer.

Dehydroepiandrosterone (DHEA), the main brain neurosteroid, has been implicated in various psychiatric disorders especially those including gender differences. We studied genetic variability in the DHEA-producing enzyme CYP17A1 in relation to anorexia nervosa (AN) susceptibility and AN-related co-morbidities. We performed analysis of 100 Israeli AN family trios accounting for CYP17A1 haplotypes characteristic of populations of European origin and studied genotype–phenotype relationships using correlation analyses and transmission disequilibrium test. Although our analysis revealed no evidence of association between CYP17A1 and AN per se, it revealed an association between specific CYP17A1 haplotypes and AN co-morbidity, specifically anxiety. We found that a common CYP17A1 haplotype (H1) was associated with higher anxiety in AN patients (Clinical Global Impression; CGI-anxiety ≥4). Moreover, H1 homozygotes were at higher risk for expressing high CGI-anxiety levels (OR = 3.7), and H1 was preferentially transmitted to AN patients with high CGI-anxiety levels (P = 0. 037). We suggest that CYP17A1 H1 haplotype may contribute to genetic predisposition to higher CGI-anxiety levels in AN patients and that this predisposition may be mediated by reduced CYP17A1 enzymatic activity and corresponding lower DHEA production.

Objective To evaluate the safety and efficacy of tamoxifen co-administration during conventional controlled ovarian hyperstimulation (COH) protocols for a fertility-preservation IVF cycle in breast cancer patients. Design Two groups: retrospective descriptive cohort study and prospective study. Setting Breast cancer oncology and fertility-preservation centers in a tertiary hospital. Patient(s) Two groups of breast cancer patients: premenopausal patients treated with adjuvant tamoxifen; and patients undergoing in vitro fertilization (IVF) for fertility preservation. Intervention(s) Fertility-preservation cycles, tamoxifen co-administration during conventional IVF. Main Outcome Measure(s) Endocrine records, and IVF results. Result(s) Estradiol (E 2 ) levels were chronically high (mean 2663 pmol/L, maximum: 10,000 pmol/L) in 38 of 46 breast cancer patients treated with adjuvant tamoxifen. Co-administration of tamoxifen (48 cycles) during conventional IVF or without tamoxifen (26 cycles), using either the long gonadotropin-releasing hormone–agonist or–antagonist protocols, resulted, respectively, in a mean of 12.65 and 10.2 oocytes retrieved, and 8.5 and 6.4 embryos cryopreserved. Average peak E 2 levels were 6,924 pmol/L and 5,093 pmol/L, respectively, but long-term recurrence risk (up to 10 years) was not increased. Conclusion(s) In breast cancer patients, co-administration of tamoxifen during conventional COH for fertility preservation does not interfere with IVF results. The high serum E 2 levels during COH should be considered safe, as it simulates the high prevalence of persistently high serum E 2 levels in premenopausal breast cancer patients safely treated with adjuvant tamoxifen.

This study investigated the correlation between in vivo serial T2-weighted magnetic resonance (MR) imaging and changes in superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities, and water, sodium ion (Na+), and potassium ion (K+) contents measured in vitro using rat brain following right middle cerebral artery occlusion in conjunction with bilateral common carotid artery (CCA) occlusion. One hour later the left CCA was released. Serial MR images showed edema developed from the outer cortex towards the center. The T2 signal intensity of the injured right cortex increased with time compared to that of the contralateral cortex. Increased Na+ and water and decreased K+ contents occurred in the injured cortex, indicating that serial T2-weighted MR imaging reflects the changes in water content and Na+ and K+ concentrations determined by biochemical techniques. GSH-Px activity was little changed. Total SOD in the injured cortex decreased 1 hour after ischemia and remained low throughout the experiment. In contrast, SOD activity in the noninfarcted left cortex also decreased after 1 hour but returned to normal after 2 hours of ischemia. Our results suggest that oxygen free radicals are important in developing ischemic brain edema and cerebral infarction.

Immunosuppressive acidic protein (IAP) has been described as a tumor marker in a number of malignant diseases. To evaluate the clinical importance of IAP in breast cancer patients, IAP serum level was determined in 75 breast cancer patients, using single radial immunodiffusion. Serum samples were also tested for CA 15-3. Cut off value for IAP was determined according to IAP serum level in 50 patients with benign, non inflammatory, diseases, and was set as 725 microgram/ml. Mean IAP serum level (623 mcg/ml) and positivity rate (20%) in 24 breast cancer patients with active disease were similar to those in 51 breast cancer patients with no evidence of disease (590 mcg/ml and 18%). The mean CA 15-3 serum level and positivity rate were significantly higher in patients with active disease (200 units/ml, 67%), compared to patients with no evidence of disease (18.3 units/ml, 6%). In our experience IAP was not found to be an effective tumor marker in breast cancer.

Open liver biopsy in a 34-year-old woman with hepatosplenomegaly showed small noncleaved cell lymphoma. Except for an enlarged spleen, there was no evidence of other sites of involvement. She was treated with combination chemotherapy and is alive and free of disease > 5 years after diagnosis. We believe this to be the first reported case in an adult of primary hepatic or hepatosplenic lymphoma of the small cleaved cell type with long-term disease-free survival.

Primary adrenal lymphoma is extremely rare. Only 75 cases have been reported in the medical literature. A case of non-Hodgkin's lymphoma originating in both adrenal glands is presented. Combination chemotherapy apparently produced complete disappearance of the primary lymphomatous lesions, but subsequently a cerebral relapse was discovered 6 months later, in the form of a solid brain mass. Cranial extension of primary adrenal lymphoma is extremely unusual, and the presentation as a solid mass seems to be unique.