Quantitative testing of pain perception in subjects with PTSD--implications for the mechanism of the coexistence between PTSD and chronic pain

Post-traumatic stress disorder (PTSD) often co-occurs with chronic pain. Neither the underlying mechanism of this comorbidity nor the nature of pain perception among subjects with PTSD is well defined. This study is the first systematic and quantitative evaluation of pain perception and chronic pain in subjects with PTSD. The study group consisted of 32 outpatients with combat- and terror-related PTSD, 29 outpatients with anxiety disorder and 20 healthy controls. Quantitative somatosensory testing included the measurement of warm, cold, light touch and heat-pain thresholds and responses to acute suprathreshold heat and mechanical stimuli. Chronic pain was characterized, and levels of PTSD and anxiety symptomatology were assessed by self-report questionnaires. Subjects with PTSD exhibited higher rates of chronic pain, more intense chronic pain and more painful body regions compared with the other two groups. PTSD severity correlated with chronic pain severity. Thresholds of subjects with PTSD were significantly higher than those of subjects with anxiety and healthy controls, but they perceived suprathreshold stimuli as being much more intense than the other two groups. These results suggest that subjects with PTSD exhibit an intense and widespread chronic pain and a unique sensory profile of hyposensitivity to pain accompanied by hyper-reactivity to suprathreshold noxious stimuli. These features may be attributed to the manner with which PTSD subjects emotionally interpret and respond to painful stimuli. Alternatively, but not mutually exclusive, the findings may reflect altered sensory processing among these subjects.     

Lineage tracing evidence for in vitro dedifferentiation but rare proliferation of mouse pancreatic beta-cells

Understanding and manipulating pancreatic beta-cell proliferation is a major challenge for pancreas biology and diabetes therapy. Recent studies have raised the possibility that human beta-cells can undergo dedifferentiation and give rise to highly proliferative mesenchymal cells, which retain the potential to redifferentiate into beta-cells. To directly test whether cultured beta-cells dedifferentiate, we applied genetic lineage tracing in mice. Differentiated beta-cells were heritably labeled using the Cre-lox system, and their fate in culture was followed. We provide evidence that mouse beta-cells can undergo dedifferentiation in vitro into an insulin-, pdx1-, and glut2-negative state. However, dedifferentiated beta-cells only rarely proliferate under standard culture conditions and are eventually eliminated from cultures. Thus, the predominant mesenchymal cells seen in cultures of mouse islets are not of a beta-cell origin.     

Telomere aggregates in trisomy 21 amniocytes

Trisomy 21 is the most common chromosomal abnormality among persons with intellectual disability, with a live birth rate of 1 in 800–1,000. As such, this abnormality may serve as a model for human disorders that result from supernumerary copies of a genomic region. Down syndrome carries an increased risk of developing acute leukemia and other malignancies. Telomeres of tumor cells nuclei tend to form aggregates (TA). This study evaluated TA formation in amniocytes from trisomy 21 pregnancies, compared with amniocytes from normal euploid pregnancies. A commercially available peptide nucleic acid telomere kit was used to evaluate TA formation, using two-dimensional fluorescence microscopy. Significantly higher frequencies of TA were found in trisomy 21 amniocytes than in amniocytes from normal pregnancies. The TAs found in trisomy 21 amniocytes apparently represent an additional parameter that reflects the high genetic instability of this syndrome and its recognized predisposition to develop leukemia and other malignancies.     

Challenges in the management of older patients with colon cancer

Most patients with colon cancer are older than 65 years. Their treatment poses multiple challenges, because they may have age-related comorbidities, polypharmacy, and physical or physiologic changes associated with older age. These challenges include limited data on the ability to predict tolerance to anticancer therapy and the appropriate use of treatment modalities in the setting of comorbidity and concurrent frailty. The low number of older patients enrolled in large clinical trials results in a paucity of evidence to guide oncologists in the appropriate management of this population. In early-stage disease, clinical dilemmas arise regarding the ability of older patients to undergo successful curative surgical procedures and the risk/benefit ratio of adjuvant chemotherapy. The management of metastatic disease raises questions regarding the clinical benefit of various anticancer therapies and the role of combination therapy with possible increased toxicity in the noncurative setting. Overall, the available evidence shows that fit older patients are able to tolerate treatment and derive similar clinical benefits to younger patients. Limited data are available to guide treatment for less-fit, more-vulnerable older patients. This lack of data leads to variations in treatment patterns in older adults, making them less likely to receive standard therapies. This review provides an overview of the available data regarding the management of older adults with colon cancer in the adjuvant and metastatic settings.     

Association between consumption of Herbalife nutritional supplements and acute hepatotoxicity

BACKGROUND/AIMS: Nutritional supplements are frequently considered to be harmless but indiscriminate use of unlabelled ingredients may lead to significant adverse reactions. METHODS: In 2004, identification of four index cases of acute hepatitis associated with Herbalife intake led to a ministry of health investigation in all Israeli hospitals. Twelve patients with acute idiopathic liver injury in association with consumption of Herbalife products were investigated. RESULTS: Eleven of the patients were females, aged 49.5+/-13.4 y. One patient had stage I primary biliary cirrhosis and another had hepatitis B. Acute liver injury was diagnosed after 11.9+/-11.1 months of initiation of Herbalife consumption. Liver biopsies demonstrated active hepatitis, portal inflammation rich with eosinophils, ductular reaction and parenchymal inflammation with peri-central accentuation. One patient developed sub-fulminant and two fulminant episodes of hepatic failure. Hepatitis resolved in eleven patients, while one patient succumbed to complications following liver transplantation. Three patients resumed consumption of Herbalife products following normalization of liver enzymes, resulting in a second bout of hepatitis. CONCLUSIONS: An association between intake of Herbalife products and acute hepatitis was identified in Israel. We call for prospective evaluation of Herbalife products for possible hepatotoxicity. Until then, caution should be exercised by consumers, especially among individuals suffering from underlying liver disease.     

The interval between cancer diagnosis among mothers and offspring in a population-based cohort

Background Familial cancers may be due to shared genes or environment, or chance aggregation. We explored the possibility that ascertainment bias influences cancer detection in families, bearing upon the time interval between diagnosis of affected mothers and offspring. Methods The Jerusalem Perinatal Study (JPS) comprises all mothers (n = 39,734) from Western Jerusalem who gave birth 1964 –1976 and their offspring (n = 88,829). After linking identification numbers with Israel’s Cancer Registry we measured the absolute time interval between initial cancer diagnoses in affected mother-offspring pairs. We tested the probability of obtaining intervals as short as those observed by chance alone, using a permutation test on the median interval. Results By June 2003 cancer had developed in 105 mother-offspring pairs within the cohort. Common sites among mothers were breast (47%), colorectal (9%), non-Hodgkin lymphoma (NHL) (8%) and cervix (7%), while for offspring in affected pairs common cancers were leukemia (12.4%), thyroid (13.3%), NHL (10.5%), breast (10.5%) and melanoma (7.6%). The median interval between diagnoses was 5.9 years, but for 33% of affected pairs the interval was ≤3 years. The probability of this occurring by chance alone was 0.03. This held true whether the offspring’s or mother’s diagnosis was first (P < 0.01). Conclusions In a population-based cohort followed for three decades, the absolute interval between the diagnosis of cancer in mothers and their offspring is shorter than expected by chance. Explanations include shared environmental exposures or the possibility that cancer ascertainment in one pair member affects health behaviors in the other resulting in early diagnosis. The latter may bias the estimation of anticipation and survival in familial cancers. Supported by Grant RO1-CA-80197 from the National Institutes of Health (NIH)     

When a sperm meets an egg: block to polyspermy

Embryonic development is initiated after the fertilizing spermatozoon enters the egg and triggers a series of events known as egg activation. Activation results in an increase in intracellular calcium concentration, cortical granule exocytosis (CGE), cell cycle resumption and recruitment of maternal mRNA. CGE is an evolutionary developed mechanism that causes modification of the zona pellucida to prevent penetration of additional spermatozoa, ensuring successful egg activation and embryo development. The egg CGE is a unique and convenient mammalian model for studying the different proteins participating at the membrane fusion cascade, which, unlike other secretory cells, occurs only once in the egg's lifespan. This article highlights a number of proteins, ascribed to participate in CGE and thus the block to polyspermy. CGE can be triggered either by a calcium dependent pathway, or via protein kinase C (PKC) activation that requires a very low calcium concentration. In a recent study, we suggested that the filamentous actin (F-actin) at the egg's cortex is a dynamic network. It can be maneuvered towards allowing CGE by activated actin associated proteins and/or by activated PKC and its down stream proteins, such as myristoylated alanine-rich C kinase substrate (MARCKS). MARCKS, a protein known to cross-link F-actin in other cell types, was found to be expressed and colocalized with actin in non-activated MII eggs. We further demonstrated MARCKS dissociation from actin after activation by ionomycin, a process that can lead to the breakdown of the actin network, thus allowing CGE. The more we know of the intricate process of CGE and of the proteins participating in it, the more the assisted reproductive procedures might benefit from that knowledge.     

Development of ALS-like disease in SOD-1 mice deficient of B lymphocytes

Several recent studies proposed a role for innate immunity and inflammation in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, possible links, if any, between disease and adaptive immunity are poorly understood. The present study probed for the role of B cells in ALS disease using the G93A-SOD-1 transgenic mouse model. In agreement with other studies, we show here that autoantibodies are detectable in SOD-1 mice. However, SOD-1 B cells did not express any altered phenotype and exhibited indistinguishable responsiveness to immunogenic stimuli relative to wild-type B cells. This was obtained for B cells isolated before, during and after the onset of ALS-like disease. Finally, to obtain an in vivo conclusion, we generated SOD-1 mice that are deficient of B cells, by crossing SOD-1 mice with Igμ-deficient mice (μMT), where B cell development is blocked at the proB stage. The meteoric assays performed on a rota-rod clearly showed the development of ALS-like disease in SOD-1 mice that are deficient of B cells not differently than in control SOD-1 mice. Our results propose that B lymphocytes do not have a major role in the pathogenesis of ALS-like disease in SOD-1 mice. S. Naor and Z. Keren have contributed equally to this study.