Comorbidity within mental disorders: a comprehensive analysis based on 145 990 survey respondents from 27 countries.

AIMS: Epidemiological studies indicate that individuals with one type of mental disorder have an increased risk of subsequently developing other types of mental disorders. This study aimed to undertake a comprehensive analysis of pair-wise lifetime comorbidity across a range of common mental disorders based on a diverse range of population-based surveys. METHODS: The WHO World Mental Health (WMH) surveys assessed 145 990 adult respondents from 27 countries. Based on retrospectively-reported age-of-onset for 24 DSM-IV mental disorders, associations were examined between all 548 logically possible temporally-ordered disorder pairs. Overall and time-dependent hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Absolute risks were estimated using the product-limit method. Estimates were generated separately for men and women. RESULTS: Each prior lifetime mental disorder was associated with an increased risk of subsequent first onset of each other disorder. The median HR was 12.1 (mean = 14.4; range 5.2-110.8, interquartile range = 6.0-19.4). The HRs were most prominent between closely-related mental disorder types and in the first 1-2 years after the onset of the prior disorder. Although HRs declined with time since prior disorder, significantly elevated risk of subsequent comorbidity persisted for at least 15 years. Appreciable absolute risks of secondary disorders were found over time for many pairs. CONCLUSIONS: Survey data from a range of sites confirms that comorbidity between mental disorders is common. Understanding the risks of temporally secondary disorders may help design practical programs for primary prevention of secondary disorders.

Post-combat adaptation: improving social support and reaching constructive growth.

BACKGROUND AND OBJECTIVES: Posttraumatic stress disorder, a commonly researched mental health outcome associated with trauma, does not develop in the majority of survivors. More common trajectories of adaptation include resilience, and posttraumatic growth (PTG). The objectives of the current study were to: (1) describe posttrauma adaptation profiles in a sample of Israeli male military veterans (N = 448); and (2) to explore the protective factors that promote constructive PTG within two profiles of posttrauma adaptation. METHODS: The study used secondary data to estimate latent profile mixture models and a series of logistic regression analyses. RESULTS: Demographic controls, combat related variables, endorsement of coping strategies, and reports of improvement in social support were not significant predictors of constructive growth in the resilient class. However, those in the struggling growth subset of the sample who reported improvement in perceived social support increased the odds of reaching constructive growth. CONCLUSION: These findings highlight the importance of tailored clinical interventions that account for more complex profiles of posttrauma adaptation; and further, provide evidence that adaptation takes place over time. Finally, these findings call for future research to continue to explore the quality of PTG and the contexts in which protective factors promote positive adaptation.

Teaching mandibular implant-Supported overdentures in dental schools in North America - a survey.

INTRODUCTION: Mandibular two-implant overdentures are considered the minimum standard of care for edentulous patients and provide an excellent performance, as well as satisfaction to the patients. Dental schools are required to promote the teaching of current treatment options in order to enable students to master state-of-the-art procedures. AIMS: The purpose of this study was to examine how the theoretical and practical aspects of mandibular two-implant overdentures are taught in dental schools in North America. METHODS: Data were collected via an online questionnaire that included questions regarding the theoretical and clinical courses, surgical procedure and imaging method. RESULTS: Of 75 schools, 36 responded to the survey. Almost all the schools teach the subject theoretically, but it is not mandatory for students to perform in most of the schools. Only a minority (23%) of the mandibular dentures made by students are implant-supported. Almost all of the schools (94%) use two implants to support overdentures, and Locator abutment is used almost exclusively. The prevalent imaging for the surgical procedure is CT scans, although 30% of the schools use panoramic radiograph. None of the schools loads the implants immediately after surgery. CONCLUSION: Some clear trends are apparent in the current survey: the use of two implants, no use of bar connectors and delayed loading of the implants. It is likely that graduates will not have sufficient clinical skills and will need continuing education to be familiar with the required procedures, both surgical and prosthetic.

Detection and characterization of carbapenemase-producing Enterobacteriaceae in wounded Syrian patients admitted to hospitals in northern Israel.

Since 2013, four hospitals in northern Israel have been providing care for Syrian nationals, primarily those wounded in the ongoing civil war. We analyzed carbapenemase-producing Enterobacteriaceae (CPE) isolates obtained from these patients. Isolate identification was performed using the VITEK 2 system. Polymerase chain reaction (PCR) was performed for the presence of bla KPC, bla NDM, and bla OXA-48. Susceptibility testing and genotyping were performed on selected isolates. During the study period, 595 Syrian patients were hospitalized, most of them young men. Thirty-two confirmed CPE isolates were grown from cultures taken from 30 patients. All but five isolates were identified as Klebsiella pneumoniae and Escherichia coli. Nineteen isolates produced NDM and 13 produced OXA-48. Among a further 29 isolates tested, multilocus sequence typing (MLST) showed that ST278 and ST38 were the major sequence types among the NDM-producing K. pneumoniae and OXA-48-producing E. coli isolates, respectively. Most were resistant to all three carbapenems in use in Israel and to gentamicin, but susceptible to colistin and fosfomycin. The source for bacterial acquisition could not be determined; however, some patients admitted to different medical centers were found to carry the same sequence type. CPE containing bla NDM and bla OXA-48 were prevalent among Syrian wounded hospitalized patients in northern Israel. The finding of the same sequence type among patients at different medical centers implies a common, prehospital source for these patients. These findings have implications for public health throughout the region.

Emotion regulation in mothers and young children faced with trauma.

The present study investigated maternal emotion regulation as mediating the association between maternal posttraumatic stress symptoms and children's emotional dysregulation in a community sample of 431 Israeli mothers and children exposed to trauma. Little is known about the specific pathways through which maternal posttraumatic symptoms and deficits in emotion regulation contribute to emotional dysregulation. Inspired by the intergenerational process of relational posttraumatic stress disorder (PTSD), in which posttraumatic distress is transmitted from mothers to children, we suggest an analogous concept of relational emotion regulation, by which maternal emotion regulation problems may contribute to child emotion regulation deficits. Child emotion regulation problems were measured using the Child Behavior Checklist-Dysregulation Profile (CBCL-DP; T.M. Achenbach & I. Rescorla, 2000), which is comprised of three subscales of the CBCL: Attention, Aggression, and Anxiety/Depression. Maternal PTSD symptoms were assessed by the Posttraumatic Diagnostic Scale (E.B. Foa, L. Cashman, L. Jaycox, & K. Perry, 1997) and maternal emotion regulation by the Difficulties in Emotion Regulation Scale (K.L. Gratz & L. Roemer, 2004). Results showed that the child's emotion regulation problems were associated with both maternal posttraumatic symptoms and maternal emotion dysregulation. Further, maternal emotion regulation mediated the association between maternal posttraumatic symptoms and the child's regulation deficits. These findings highlight the central role of mothers' emotion regulation skills in the aftermath of trauma as it relates to children's emotion regulation skills. The degree of mothers' regulatory skills in the context of posttraumatic stress symptoms reflects a key process through which the intergenerational transmission of trauma may occur. Study results have critical implications for planning and developing clinical interventions geared toward the treatment of families in the aftermath of trauma and, in particular, the enhancement of mothers' emotion regulation skills after trauma.

A novel anchoring system for colonic stents: a pilot in vivo study in a porcine model.

BACKGROUND: Colorectal stents have a proven role in colorectal cancer as palliative care or a bridge to surgery. However, their efficacy and anchoring to the tissue varies according to stent design with stent migration rates up to 50 %. We present preliminary in vivo results of a new end-luminal anchoring system for stent fixation to the rectal canal. The aim was to assess the efficacy and safety of the stent using the anchoring system while subjecting the device to daily abdominal pressures related to daily activities in a porcine animal model. METHODS: Ex vivo anatomical and physical studies were performed to improve the system's structure and safety. Four female pigs were followed for the acute and chronic (16 weeks) period. Two animals were euthanized and underwent en-bloc pelvic visceral excision and histopathological examination. Device fixation time, animal behavior, device patency, anoscopic examination and histopathological features were assessed. RESULTS: Mean anchoring time was 13.83 weeks (standard error ± 1.38 weeks). One of the animals experienced early device expulsion with no complications. No obstruction was noted in any of the animals. Macroscopic examination revealed mild focal submucosal scarring in one animal and a normal examination in the other. Hematoxylin and eosin staining revealed mucosal ulceration and mixed inflammatory cell infiltrate, with no signs of granulomata, foreign body giant cell reaction or microabscess formation. CONCLUSIONS: A novel fixation device designed for long-term intrarectal implantation was well tolerated and maintained anal canal patency without migration. Larger studies are needed before its implementation in humans.

Post anterior rectal resection syndrome--a retrospective multicentre study.

AIM: The long-term effects of surgical and non-surgical factors on increased stool frequency and incontinence following anterior resection have been variably reported. We investigated the effects of surgical characteristics on symptoms at 1 month and more than 1 year postoperatively following anterior resection of the rectum. METHOD: In this retrospective study of patients who underwent anterior resection of the rectum during 2002-2006, patients were interviewed regarding symptoms at 1 month and more than 1 year postoperatively. Anterior resection of the rectum syndrome (ARRS) is more simply defined as incontinence and/or frequent bowel movements after surgery and graded as severe, moderate or mild. RESULTS: Of the 165 patients who underwent anterior resection for rectal cancer during the study period, 106 were included in the analysis. The median follow-up period was 3.4 years (range 13-72 months). ARRS had a high prevalence 1 month postoperatively (55.6%) but abated in over half the cases at 1 year postoperatively. The likelihood of development of early but not late ARRS was associated with the anastomotic level suggesting adaptation. ARRS and continence were unaffected by total mesorectal excision, the use of adjuvant radiation or chemotherapy, patient age or disease stage. CONCLUSION: The level of anastomosis in anterior resection of the rectum had a significant effect on the prevalence of ARRS using a new simpler definition 1 month after surgery but not 1 year or more postoperatively. Further data on neorectal reservoir reconstruction using the simpler ARRS definition are required.

Low anterior resection syndrome (LARS): cause and effect and reconstructive considerations.

Between 25 and 80% of patients undergoing a low or very low anterior resection will suffer postoperatively, from a constellation of symptoms including fecal urgency, frequent bowel movements, bowel fragmentation and incontinence, collectively referred to as the low anterior resection syndrome (LARS). The etiology of LARS is multifactorial with the potential of sphincter injury during anastomosis construction, alterations in anorectal physiology, the development of a pudendal neuropathy, and a lumbar plexopathy with exacerbation of symptoms if there is associated anastomotic sepsis or the use of adjuvant and neoadjuavnt therapies. The symptoms of LARS may be obviated in part by the construction of a neorectal reservoir which may take the form of a colonic J-pouch, a transverse coloplasty, or a side-to-end anastomosis. This review outlines the factors contributing to LARS symptomatology along with the short- and medium-term functional results of comparative trials with the different types of neorectal reconstructions.

A new colonic lavage system to prepare the colon for colonoscopy: a retrospective study.

BACKGROUND: One of the most unpleasant and sometimes difficult elements of colonoscopic examination is the bowel preparation which is usually performed 6 or more hours prior to the examination ("early" preparation), causing many patients to refrain from undergoing this procedure. We present a novel technique for bowel preparation that begins approximately 30 min prior to the introduction of the colonoscope and eliminates the need for significant pre-procedure preparation. METHODS: The medical records of all consecutive patients who underwent colonoscopy without "early" preparation (CWEP) from May 2009 through June 2010 were retrospectively reviewed. The procedure was performed using a novel cleansing device, the "ColonoScoPrep™", with which the colon is prepared about half an hour prior to insertion of the colonoscope. The only medication required is two to three bisacodyl tablets the night before. The quality of bowel preparation was graded as excellent, good, satisfactory, or poor, and patient satisfaction was assessed according to a prospective protocol. RESULTS: During this period, 125 patients underwent CWEP. Of these, 110 (89.4 %) patients had an excellent or good preparation, permitting complete colonoscopic examination unimpeded by fecal matter. In 11 patients, preparation was satisfactory, in 2 it was poor and in 2, colonoscopy was not completed due to unsatisfactory preparation. None of the patients suffered from abdominal pain or cramps during or after the CWEP and none had post-colonoscopy diarrhea. All patients were satisfied with the procedure. CONCLUSIONS: Despite the fact that the study is retrospective, CWEP appears safe and easy to perform. A prospective study comparing conventional bowel preparation and CWEP is now underway.

Colorectal carcinoma in inflammatory bowel disease: a comparison between Crohn's and ulcerative colitis.

AIM: The study assessed the clinicopathological features and survival rates of inflammatory bowel disease (IBD) patients with colorectal carcinoma (CRC), which accounts for ∼ 15% of all IBD associated death. METHOD: The medical records of patients operated on for CRC in three institutions between 1992 and 2009 were reviewed, and those with Crohn's colitis (CC) and ulcerative colitis (UC) were identified. Data on age, gender, disease duration, colitis severity, surgical procedure, tumour stage and survival were retrieved. RESULTS: Fifty-three patients (40 UC and 13 CC, 27 men, mean age at operation 54 years) were found. All parameters were comparable between the groups. Mean disease duration before CRC was 22.7 years for UC and 16.6 years for CC patients (P = 0.04). CRC was diagnosed preoperatively in 43 (81%) patients. Twenty-eight patients had colon cancer, 23 had rectal cancer and two patients had more than one cancer. All malignancies were located in segments with colitis. Over one-half were diagnosed at an advanced stage (36% stage III; 17% stage IV). At a mean follow up of 56 ± 65 months, 60% were alive (54% disease free) and 40% were dead from cancer-related causes. The 5-year survival rate was 61% for the UC and 37% for the CC patients (P = NS). CONCLUSION: CRC in IBD patients is frequently diagnosed at an advanced stage, a factor that contributes to poor prognosis. The risk of CRC in CC patients is comparable to those with UC. Long-term surveillance is recommended for patients with long-standing CC and UC.

Resistance or sensitivity of Wilms' tumor to anti-FZD7 antibody highlights the Wnt pathway as a possible therapeutic target.

Wilms' tumor (WT), the most frequent renal solid tumor in children, has been linked to aberrant Wnt signaling. Herein, we demonstrate that different WTs can be grouped according to either sensitivity or resistance to an antibody (Ab) specific to frizzled7 (FZD7), a Wnt receptor. In the FZD7-sensitive WT phenotype, the Ab induced cell death of the FZD7(+) fraction, which in turn depleted primary WT cultures of their clonogenic and sphere-forming cells and decreased in vivo proliferation and survival on xenografting to the chick chorio-allantoic-membrane. In contrast, FZD7-resistant WT in which no cell death was induced showed a different intra-cellular route of the Ab-FZD7 complex compared with sensitive tumors and accumulation of ß-catenin. This coincided with a low sFRP1 and DKK1 (Wnt inhibitors) expression pattern, restored epigenetically with de-methylating agents, and lack of ß-catenin or WTX mutations. The addition of exogenous DKK1 and sFRP1 to the tumor cells enabled the sensitization of FZD7-resistant WT to the FZD7 Ab. Finally, although extremely difficult to achieve because of dynamic cellular localization of FZD7, sorting of FZD7(+) cells from resistant WT, showed them to be highly clonogenic/proliferative, overexpressing WT 'stemness' genes, emphasizing the importance of targeting this fraction. FZD7 Ab therapy alone or in combination with Wnt pathway antagonists may have a significant role in the treatment of WT via targeting of a tumor progenitor population.

The effect of neoadjuvant Imatinib therapy on outcome and survival after rectal gastrointestinal stromal tumour.

AIM: The study aimed to characterize the pathological and clinical response of rectal gastrointestinal stromal tumours (GISTs) to neoadjuvant Imatinib. METHOD: The medical records of patients with rectal GISTs who were diagnosed and treated in five medical centres in Israel between January 2002 and January 2009 were retrospectively examined. Twelve patients who fulfilled the inclusion criteria of nonmetastatic rectal GIST for which preoperative neoadjuvant treatment with Imatinib was considered were suitable for enrollment. RESULTS: Of the 12 patients, nine received neoadjuvant treatment with Imatinib. The three patients who had immediate surgery were excluded. There were five men and four women with a median age of 63 years and a median follow up of 32 months. All tumours were located in the lower two-thirds of the rectum. One patient had a complete clinical response, six had a partial response and two had stable disease. Seven patients subsequently underwent surgery; six had an R0 resection and one had an R1 resection. Three patients had recurrence. There was no disease-related mortality. The reduction in both tumour size and mitotic activity during preoperative Imatinib therapy was significant. CONCLUSION: Preoperative Imatinib therapy can shrink large rectal GISTs, improving the chances of successful radical surgery and decreasing the risk of considerable morbidity.

Mifepristone (RU486), a pure antiprogesterone drug, in combination with vinblastine for the treatment of progesterone receptor-positive desmoid tumor.

We report the case of a patient who developed a desmoid tumor following total proctocolectomy and J-pouch reconstruction that was unresponsive to any medical treatment. Based on estrogen receptor alpha (ERalpha) and progesterone receptor (PR) evaluation (ERalpha-negative, but PR-positive), treatment with mifepristone, a pure antiprogesterone drug, was initiated, and partial tumor regression was achieved.

Long-term outcome of loose seton for complex anal fistula: a two-centre study of patients with and without Crohn's disease.

OBJECTIVE: Complex anal fistulas traverse a significant portion of the external sphincter muscle, making their treatment a surgical challenge. Several surgical options are used with conflicting results. The aim of this study was to analyse the results of permanent loose seton in the management of high anal fistulas in Crohn's disease (CD) patients and two-stage seton fistulotomy in patients without CD. METHOD: We retrospectively reviewed the clinical records of 77 patients with complex anal fistula treated by loose seton over a 4-year period, in two medical centres. Recorded parameters included demographics, medical history, type of fistula, disease duration, previous surgery, morbidity, recurrence and mortality. RESULTS: Sixty patients without CD underwent 107 fistula-related surgical procedures, and 17 CD patients underwent 29 procedures. Early postoperative complications were recorded in eight (10%) patients. Perioperative complications, mainly local sepsis or bleeding, were recorded in eight (10%) patients. Long-term complications were observed in nine non-CD and four CD patients. During a median follow-up period of 24 months, the recurrence rate was 40% in CD patients and 47% in patients without CD. Five patients (four non-CD patients and one CD patient) developed some degree of faecal incontinence. CONCLUSION: The fistula recurrence rate following two-stage seton fistulotomy in non-CD patients was high. In CD patients the use of permanent loose seton is effective in controlling local sepsis in about half of patients and has low rates of subsequent incontinence.

Young-age onset of colorectal cancer in Israel.

AIM: The study was conducted to investigate the differences in clinical-pathological, ethnic, and demographic presentations and the expression of mismatch repair proteins in a cohort of young-onset (50 years) with colorectal cancer. MATERIALS AND METHODS: Clinical, demographic, and histopathological data of patients with colorectal cancer were collected retrospectively from medical records and pathology reports. RESULTS: Ninety patients, 50 years of age or younger with a mean age of 42 years were compared with a group of 190 patients above 50 years of 50 (see Table 1). Sixty percent of the young-onset patients were females, compared to 40% in the older age group (P = 0.02). Twenty-one percent of the young-onset patients were Arabs as compared to 2% of older-onset patients (P = 0.001). Younger patients displayed a higher percentage of mucinous cancers and a higher percentage of diagnosis at an advanced stage of disease; 40% of young-onset versus 31% of older-onset patients presented Duke's stages C and D (P = 0.02). CONCLUSIONS: Younger age of onset colorectal cancer in our cohort of Israeli patients is associated with higher percentage of Arab patients, mucinous cancers, female gender, and advanced stage at diagnosis.

Age-dependent spatial memory loss can be partially restored by immune activation.

Aging is often associated with a decline in hippocampus-dependent spatial memory. Here, we show that functional cell-mediated immunity is required for the maintenance of hippocampus-dependent spatial memory. Sudden imposition of immune compromise in young mice caused spatial memory impairment, whereas immune reconstitution reversed memory deficit in immune-deficient mice. Analysis of hippocampal gene expression suggested that immune-dependent spatial memory performance was associated with the expression of insulin-like growth factor (Igf1) and of genes encoding proteins related to presynaptic activity (Syt10, Cplx2). We further showed that memory loss in aged mice could be attributed to age-related attenuation of the immune response and could be reversed by immune system activation. Homeostatic-driven proliferation of lymphocytes, which expands the existing T cell repertoire, restored spatial memory deficits in aged mice. Thus, our results identify a novel function of the immune system in the maintenance of spatial memory and suggest an original approach for arresting or reversing age-associated memory loss.

Effect of electrocautery vs. scalpel on fascial mechanical properties after midline laparotomy incision in rats.

BACKGROUND: The method of midline laparotomy incision and closure remains a complex surgical problem. OBJECTIVE: To compare the mechanical properties at the interface of midline laparotomy incision made by scalpel versus electrocuting current in rats. METHODS: A sharp midline laparotomy incision was made in 60 Wistar female rats using a scalpel or electrocautery to open the fascia. The fascial and skin wounds were closed separately with a continuous nylon. Fascial specimens were analyzed for mechanical properties at the midline incision using a loading machine. The load-extension curve was recorded during tensile loading at a steady extension rate of 15 mm/min. RESULTS: There was no statistically significant difference between the two groups in either wound-bursting force (PPEAK) or the strain energy spent until the point of measured PPEAK. Each load-extension curve showed a characteristic pattern in all rats. Tissue stiffness was greater in the scalpel group than in the electrocautery group (P = 0.02). Correlations were found between tissue stiffness and strain energy, between tissue stiffness and bursting force, and between bursting force and strain energy. CONCLUSIONS: While tissue stiffness was greater when a scalpel was used compared to electrocuting to incise the midline abdominal fascia in rats, there was no difference in the bursting force required to disrupt the wound.

Telomeric protein Pin2/TRF1 as an important ATM target in response to double strand DNA breaks.

ATM mutations are responsible for the genetic disease ataxia-telangiectasia (A-T). ATM encodes a protein kinase that is activated by ionizing radiation-induced double strand DNA breaks. Cells derived from A-T patients show many abnormalities, including accelerated telomere loss and hypersensitivity to ionizing radiation; they enter into mitosis and apoptosis after DNA damage. Pin2 was originally identified as a protein involved in G(2)/M regulation and is almost identical to TRF1, a telomeric protein that negatively regulates telomere elongation. Pin2 and TRF1, probably encoded by the same gene, PIN2/TRF1, are regulated during the cell cycle. Furthermore, up-regulation of Pin2 or TRF1 induces mitotic entry and apoptosis, a phenotype similar to that of A-T cells after DNA damage. These results suggest that ATM may regulate the function of Pin2/TRF1, but their exact relationship remains unknown. Here we show that Pin2/TRF1 coimmunoprecipitated with ATM, and its phosphorylation was increased in an ATM-dependent manner by ionizing DNA damage. Furthermore, activated ATM directly phosphorylated Pin2/TRF1 preferentially on the conserved Ser(219)-Gln site in vitro and in vivo. The biological significance of this phosphorylation is substantiated by functional analyses of the phosphorylation site mutants. Although expression of Pin2 and its mutants has no detectable effect on telomere length in transient transfection, a Pin2 mutant refractory to ATM phosphorylation on Ser(219) potently induces mitotic entry and apoptosis and increases radiation hypersensitivity of A-T cells. In contrast, Pin2 mutants mimicking ATM phosphorylation on Ser(219) completely fail to induce apoptosis and also reduce radiation hypersensitivity of A-T cells. Interestingly, the phenotype of the phosphorylation-mimicking mutants is the same as that which resulted from inhibition of endogenous Pin2/TRF1 in A-T cells by its dominant-negative mutants. These results demonstrate for the first time that ATM interacts with and phosphorylates Pin2/TRF1 and suggest that Pin2/TRF1 may be involved in the cellular response to double strand DNA breaks.

Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response.

BRCA1 encodes a familial breast cancer suppressor that has a critical role in cellular responses to DNA damage. Mouse cells deficient for Brca1 show genetic instability, defective G2-M checkpoint control and reduced homologous recombination. BRCA1 also directly interacts with proteins of the DNA repair machinery and regulates expression of both the p21 and GADD45 genes. However, it remains unclear how DNA damage signals are transmitted to modulate the repair function of BRCA1. Here we show that the BRCA1-associated protein CtIP becomes hyperphosphorylated and dissociated from BRCA1 upon ionizing radiation. This phosphorylation event requires the protein kinase (ATM) that is mutated in the disease ataxia telangiectasia. ATM phosphorylates CtIP at serine residues 664 and 745, and mutation of these sites to alanine abrogates the dissociation of BRCA1 from CtIP, resulting in persistent repression of BRCA1-dependent induction of GADD45 upon ionizing radiation. We conclude that ATM, by phosphorylating CtIP upon ionizing radiation, may modulate BRCA1-mediated regulation of the DNA damage-response GADD45 gene, thus providing a potential link between ATM deficiency and breast cancer.