Combined environmental stress and physiological strain indices for physical training guidelines

The purpose of this study was to develop guidelines based on the previously described environmental stress index (ESI) and physiological strain index (PSI) for work-rest cycles (WRC) during training, especially in the military. The ESI was introduced as a potential substitute for the Wet Bulb Globe Temperature Index because of the very high correlation coefficients between them. The ESI is constructed from the fast-reading meteorological response sensors ambient temperature (Ta), relative humidity (RH), and global radiation (GR), which require only a few seconds to reach equilibrium. The ESI, the first stress index using direct measurements of solar radiation (SR), is calculated as follows: ESI = 0.63Ta - 0.03RH + 0.002SR + 0.0054 (Ta x RH) - 0.073(0.1 + SR)(-1). The PSI is based on heart rate (HR) and rectal temperature (Tre) and can indicate heat strain online and analyze databases. The PSI is constructed as follows: PSI = 5(Tret - Tre0) x (39.5 - Tre0)(-1) + 5(HRt - HR0) x (180 - HR0)(-1), where Tre0 and HR0 are the initial Tre and HR, and Tret and HRt are simultaneous measurements taken at any time. The PSI is scaled from 0 to 10, whereby the respective variables, PSIHR and PSITre, representing the cardiovascular and thermoregulation systems, can contribute up to five units to the overall strain assessment. To integrate the PSI and ESI, we decided to use only the PSIHR component, which represents the metabolic rate and the strain reflected by the cardiovascular system. Furthermore, PSIHR is easier to measure, is easier to implement, and simplifies the integration with ESI. Concomitantly, PSIHR categorizes the strain between 0 and 5, the higher the value, the higher the strain. We believe that the use of the PSI WRC values will help in decreasing the risk of future heat injuries.     

Maximum tolerable dose and low-dose metronomic chemotherapy have opposite effects on the mobilization and viability of circulating endothelial progenitor cells

There is growing evidence that vasculogenesis (progenitor cell-derived generation of new blood vessels) is required for the growth of some neoplastic diseases. Here we show that the administration of cyclophosphamide (CTX) at the maximum tolerable dose with 21-day breaks or at more frequent low-dose (metronomic) schedules have opposite effects on the mobilization and viability of circulating endothelial progenitors (CEPs) in immunodeficient mice bearing human lymphoma cells. Animals treated with the maximum tolerable dose CTX experienced a robust CEP mobilization a few days after the end of a cycle of drug administration, and tumors rapidly became drug resistant. Conversely, the administration of metronomic CTX was associated with a consistent decrease in CEP numbers and viability and with more durable inhibition of tumor growth. Our findings suggest that metronomic low-dose chemotherapy regimens are particularly promising for avoiding CEP mobilization and, hence, to potentially reduce vasculogenesis-dependent mechanisms of tumor growth.     

Puberty as a risk factor for less favorable visual outcome in idiopathic intracranial hypertension

PURPOSE: To test the hypothesis that puberty is a risk factor for poorer visual outcome in idiopathic intracranial hypertension (IIH). DESIGN: Retrospective chart review case series. METHODS: Setting: Tertiary referral center, neuro-ophthalmology unit. Patient population: Ninety-six patients with IIH followed for a minimum of one year. Observation: Age (grouped into prepubertal, pubertal, teenage, or adult), obesity, initial intracranial pressure (ICP), measurements and presence of hypertension, anemia, or renal failure were correlated with final visual outcome using chi(2), stepwise logistic regression, and model-selection log linear analyses. Main outcome measures: Visual outcome was graded into "excellent" -- no evidence of an optic neuropathy or any permanent visual field defect in either eye, "moderate"-- evidence of an optic neuropathy and/or a mild (nasal constriction) visual field defect, or "poor outcome" (peripheral constriction) -- permanent visual field defect. RESULTS: Outcome data were complete for 96 patients. Moderate to poor visual outcome, as opposed to excellent, was significantly associated with puberty (P = .007 using the gender-specific definition of puberty, .0002 using the broad definition). Moderate-poor visual outcome occurred in none of seven IIH patients of prepubertal age (<9 years), in 15 of 26 patients presenting between nine to 16 years, in two of six patients aged 17 to 22 years, and in seven of 57 adult patients over the age of 23 years. CONCLUSIONS: In this series of 96 patients with IIH, visual outcome was less favorable in pubertal patients than in prepubertal, teenage, and adult patients. We recommend that clinicians maintain a high index of awareness when caring for pubescent children with IIH.     

Comparison of symptoms and treatments of adults and adolescents with borderline personality disorder

The purpose of this paper was to characterize adolescent borderline personality disorder (BPD) and compare it to adult BPD. A retrospective chart review of 20 adolescent and 20 adult BPD patients was conducted. The retrieved data included demographics, history features, symptoms, observations made during hospitalization and treatments. There were many similarities between the two groups. The differences included the number of report pages during hospitalization (p<0.05), of current self-mutilation (p=0.051), of past and present obsessive-compulsive symptoms (p=0.02 and p=0.03) and of past escapes (p=0.006). Adults had more alcohol abuse (p=0.02). There was a correlation between the number of anti-psychotic drug trials and the length of hospitalization among adolescents, and a correlation between the number of antidepressant and anxiolytic drug trials and the length of hospitalization among adults. Our findings support the general similarity of BPD between adolescents and adults. The differences in pharmacotherapy and several clinical observations warrant further study.     

Cellular and molecular surrogate markers to monitor targeted and non-targeted antiangiogenic drug activity and determine optimal biologic dose

Perhaps the most significant recent advance in oncology therapeutics has been the approval of various "molecularly targeted" anti-cancer drugs. Currently, there are a large number of similar drugs in early or late stage development, including antiangiogenic agents. Clinical development of such drugs suffers from several handicaps including determining whether a patient's cancer expresses the target and is functionally contributing to cancer growth, monitoring biologic activity, and determining optimal biologic dose. The last problem is related to the low frequency of objective tumor responses (tumor shrinkage) caused by such drugs, or the lack of dose limiting toxicities necessary to define a maximum tolerated dose (MTD), or expression of optimal therapeutic activity at doses below the MTD, when one can be defined. These problems necessitate the development of alternative pharmacodynamic surrogate markers. Here we summarize several such promising markers for monitoring targeted antiangiogenic activity, and establishing optimal therapeutic/biologic dosing. The first is molecular--plasma VEGF--levels of which are rapidly and significantly increased in a dose dependent manner after injection of normal or tumor bearing mice with anti-VEGFR-2 antibodies. The second is a cellular marker, and more generic in nature--circulating VEGF receptor-2 positive cells found in peripheral blood, some of which may be circulating endothelial progenitor cells. Levels of such cells are suppressed in a dose dependent manner which correlate with previously determined optimal biologic/therapeutic anti-tumor activity of various antiangiogenic drugs or treatments. Finally, another promising marker we discuss is soluble VEGFR-2.     

Down-regulation of DNA mismatch repair proteins in human and murine tumor spheroids: implications for multicellular resistance to alkylating agents

Similar to other anticancer agents, intrinsic or acquired resistance to DNA-damaging chemotherapeutics is a major obstacle for cancer therapy. Current strategies aimed at overcoming this problem are mostly based on the premise that tumor cells acquire heritable genetic mutations that contribute to drug resistance. Here, we present evidence for an epigenetic, tumor cell adhesion-mediated, and reversible form of drug resistance that is associated with a reduction of DNA mismatch repair proteins PMS2 and/or MLH1 as well as other members of this DNA repair process. Growth of human breast cancer, human melanoma, and murine EMT-6 breast cancer cell lines as multicellular spheroids in vitro, which is associated with increased resistance to many chemotherapeutic drugs, including alkylating agents, is shown to lead to a reproducible down-regulation of PMS2, MLH1, or, in some cases, both as well as MHS6, MSH3, and MSH2. The observed down-regulation is in part reversible by treatment of tumor spheroids with the DNA-demethylating agent, 5-azacytidine. Thus, treatment of EMT-6 mouse mammary carcinoma spheroids with 5-azacytidine resulted in reduced and/or disrupted cell-cell adhesion, which in turn sensitized tumor spheroids to cisplatin-mediated killing in vitro. Our results suggest that antiadhesive agents might sensitize tumor spheroids to alkylating agents in part by reversing or preventing reduced DNA mismatch repair activity and that the chemosensitization properties of 5-azacytidine may conceivably reflect its role as a potential antiadhesive agent as well as reversal agent for MLH1 gene silencing in human tumors.     

The splenic microenvironment is a source of proangiogenesis/inflammatory mediators accelerating the expansion of murine erythroleukemic cells

The stromal compartments of hematopoietic organs (eg, spleen) are known to influence the viability and growth of diseased hematopoietic progenitors. Here we have used Friend murine leukemia virus (F-MuLV)-induced erythroleukemia to investigate factors of the splenic microenvironment that may make it fertile for the expansion and survival of malignant erythroblasts. We found that splenectomized, erythroleukemic mice exhibited extended survival compared with age-matched sham controls. In vitro, the proliferation of primary erythroleukemic cells cocultured with leukemic-derived splenic adherent cells or their conditioned media was found to be significantly higher than that observed in cocultures with healthy-derived adherent splenic cells. Cytokine protein arrays revealed that F-MuLV-infected splenocytes secreted elevated levels of interleukin-6 (IL-6), vascular endothelial growth factor-A (VEGF-A), macrophage chemoattractant protein-5 (MCP-5), soluble tumor necrosis factor receptor-1 (sTNFR1), IL-12p70, tumor necrosis factor-alpha (TNF-alpha), and IL-2 over normal splenocytes. Medium supplemented with both VEGF-A and MCP-5 could sustain proliferation of primary erythroleukemic cells in vitro, and significant proliferative suppression was observed upon addition of neutralizing antibodies to either of these factors. Furthermore, in vivo administration of a neutralizing antibody to VEGF-A extended survival times of erythroleukemic mice in comparison with controls. These findings suggest that VEGF-A and MCP-5 are potentially pivotal paracrine mediators occurring within the diseased splenic microenvironment capable of promoting disease acceleration and expansion of erythroleukemic blasts.     

A multidisciplinary field hospital as a substitute for medical hospital care in the aftermath of an earthquake: the experience of the Israeli Defense Forces Field Hospital in Duzce, Turkey, 1999

The damage created by an earthquake can overwhelm local health services, and damage to clinics and hospitals can render them useless. After an earthquake, even undamaged medical facilities cannot be used for a period of time if there is a risk of aftershocks and collapse. In such a situation, there may be calls for international health teams--but what constitutes the optimal medical aid a few days after the event? Does a military field hospital fill the "gap" in the local healthcare system? On 12 November 1999, a 7.2 magnitude earthquake struck Duzce, Turkey. All of the medical activities of the responding Israeli Defense Forces (IDF) mission team field hospital in Duzce, Turkey were recorded and evaluated. A total of 2,230 patient contacts occurred at the field hospital during the nine days it operated. Most of the patients who presented (90%) had non-traumatic medical, pediatric, or gynecological problems unrelated to the earthquake. The IDF hospital offered medical care provided by specialists, hospitalization, and surgical abilities, which Duzce's hospitals could not offer until two weeks after the earthquake. These results strengthen the importance of a multidisciplinary, versatile, field hospital as an aid to an earthquake-affected population during the first few weeks after an earthquake.     

Postnatal regulation of ZnT-1 expression in the mouse brain

We have characterized the postnatal development of ZnT-1, a putative zinc transporter, in the mouse brain with respect to chelatable zinc in four distinct brain areas: cerebral cortex, hippocampus, olfactory bulb and cerebellum. At birth, both zinc and ZnT-1 immunoreactivity were nearly undetectable. Beginning at the end of the first postnatal week, ZnT-1 expression increased significantly in all areas examined except the cerebellum, which contains virtually no synaptic zinc. Moreover, neurons immunoreactive for ZnT-1 were typically present in areas rich in synaptic zinc, which increased in parallel with ZnT-1. In the cerebellum, in contrast, Purkinje cells exhibited robust immunoreactivity for ZnT-1 only in the second postnatal week. While the parallel development of zinc and ZnT-1 in forebrain regions supports a direct role for synaptic zinc in regulating ZnT-1 expression, ZnT-1 in cerebellar Purkinje cells could indicate that expression of this zinc transporter may also be regulated by a non-synaptic pool of zinc or by other mechanism(s). The striking developmental regulation of ZnT-1 expression together with synaptic zinc indicates that ZnT-1 may play a key role in protecting developing neurons against potentially toxic zinc.