In addition to depleted uranium other war-related environmental factors have been studied and linked directly or indirectly with the increasing prevalence of birth defects. However, the reviewed studies and the available research evidence do not provide a clear increase in birth defects and a clear indication of a possible environmental exposure including depleted uranium although the country has been facing several environmental challenges since 1980.An increased prevalence of birth defects was allegedly reported in Iraq in the post 1991 Gulf War period, which was largely attributed to exposure to depleted uranium used in the war. This has encouraged further research on this particular topic. This paper reviews the published literature and provided evidence concerning birth defects in Iraq to elucidate possible environmental exposure. In addition to published research, this review used some direct observation of birth defects data from Al-Ramadi Maternity and Paediatric Hospital in Al-Anbar Governorate in Iraq from1 Birth defects are still the leading cause of perinatal mortality and childhood disability in developed countries . In contThe causes of most birth defects remain unknown, but the growing literature indicates that environmental factors may cause genetic mutations and interact with genetic factors predisposing to birth defects . Thus, mst July 2000 through 30th June 2002 where a total of 12831 live births and stillbirths at hospital were included. All live born neonates were physically examined by a pediatrician during the first three days of delivery, and birth defects were reported. Stillborn fetuses were only physically examined without autopsy. This study is referred to as ‘Al-Anbar study’ in this review.Workers allegedly reported a high prevalence of birth defects in Basrah (south of Iraq) in the post 1991 Gulf War period, which was attributed to exposure to depleted uranium (DU) used in the war ,7. This Al-Anbar study revealed a rate of 8.5 birth defects per 1000 births. Similar rates were reported in Basrah in 1998 (7.76 per 1000 births) , Turkey Central nervous system defects were the most common types of birth defects among live births. In Al-Anbar governorate it constituted 55% with a rate of 4.6 per 1000 live births. Similar rates were reported in Basrah for the period 1999–2000 (4.35 per 1000 births) . RecentlThe root causes of many adverse pregnancy outcomes are not well understood, but there is growing evidence that the environment can play an important role. ‘Environment” is a broad term that includes familiar contributors such as nutrition, adequacy of prenatal care, smoking and alcohol use, maternal age, and socioeconomic disparities, as well as less familiar contributors including pollution and chemical agents encountered both indoors and outdoors. In many cases, two or more environmental factors may be interrelated or synergistic .Based on the current knowledge, the etiology of about 40% of birth defects has been recognized to date. Among various birth defects of known etiology, around 36% are caused exclusively by genetic factors, whereas 50–75% results from complex gen-environmental interactions . Around Geographical variations in prevalence reported by malformation registries may give clues to etiological factors when they represent true differences, as is the observed variation in prevalence rates of neural tube defects in different regions of the world . GeograpPrior to the first Gulf War (1980–1988 Iraq-Iran War) and the second Gulf War (1991 Gulf War) in particular, compared to the west, the Iraqi environment was surely more pristine and environmental challenges were different . The 199Much attention has recently focused on worldwide role of DU. The development of DU munitions began around 1959 in the United States and in the early 1960s in the United Kingdom . In the The United States military deployed DU munitions for the first time during the 1991 Gulf War. Depleted Uranium weapons were also used in 1994–1995 war in Bosnia, the 1999 war in Kosovo, the United States 2002 invasion of Afghanistan and the 2003 invasion of Iraq . ApparenMilitary personnel, civilians and the DU munitions producers are being exposed to the DU aerosols that are generated. The detailed pathways, by which environmental DU can be internalized and reach reproductive cells, are not yet fully elucidated. While research on molecular, cellular and animal model level suggests plausibility , there iPreliminary epidemiological studies carried out by community activists in the United States reported hydrocephalic births in a sparsely population rural are downwind of a DU-weapons testing sites . These eThere is a possibility of genetic damage resulting from exposure to some forms of radiation emitted from particles such as those deposited by DU weapons . Animal Basrah is in the region that was heavily exposed to bombardment with DU during the 1991 Gulf War . Two stuThe low pre 1991 Gulf War baseline incidence of birth defects reported in the Basrah registry studies (3.04 per 1000 births) ,7 does nIn spite of what has been reported, theoretically Marshall  used matst November 2007 and 1st November 2008 giving an incidence of 3.3 per 1000 births [Little is known about the types of weapons deployed in Fallujah of Al-Anbar governorate during the first major US assault in April 2004 and during Operation Phanum Fury, the second major assault in November 2004. However, reports began to emerge after 2005 of sudden increase in cancer and leukemia rates . In Al-R0 births . Contami0 births .The issue of disentangling the role of parental exposure to DU from that of exposure to other potential teratogens is serious and complex which needs to be resolved through extensive laboratory and epidemiological researches .In Iraq exposure to other potential teratogens during 1991 Gulf War could not be excluded as the country was highly exposed to chemical carcinogens of relevance to the war. The retreating Iraqi forces set fires to Kuwaiti oil fields, and the generated smoke was carried by prevailing wind over Iraq  The enviPAHS are potent atmospheric pollutants occur in oil, coal and tar deposits and are produced as byproducts of fuel burning. As a pollutant, they are of concern because some compounds have been identified as carcinogenic, mutagenic and teratogenic. Several studies have reported an association between exposure to PAHs air and adverse birth outcomes including low birth weight and prematurity ,42. StudChlorinated dibenzo-p-dioxins (CDDs) is a family of released compounds commonly known as chlorinated dioxins. The most toxic compound among CDDs is the 2,3,7,8,TCDD which is odorless . DioxinsThe International Agency for Research on Cancer (IARC), a part of the WHO considered in 1997, 2,3,7,8TCDD a human carcinogen. The health effects of CDDs including birth defects and cancer that observed in animal studies cannot be ruled out in human ,50. AfteThe possibility of exposure to other specific local risk or causal factors particularly heavy metals needs to be investigated. Animal teratogenesis by a variety of heavy metals and human teratogenesis by at least lead and mercury are long established . In IraqThe Fallujah study revealed significant high levels of Ca, Mg, Co, Fe, Mn, V, Zn, Sr, Al, Ba, Bi, Ga, Pb, Hg and Pd in the hair of parents of children with birth defect in comparison with published mean levels in an uncontaminated population in Sweden. Of these only Hg could be considered by the authors as a possible cause of congenital anomaly .th, 1988 the Iraqi forces attached Halabja with chemical weapons and artillery fire.Exposure to chemical agents in the 1980s is another source of exposure. Chemical agents were certainly used during the first Gulf War and in Iraqi Kurdistan against indigenous Iraqi Kurds in 1988; mustard gas being one of these agents ,61. On tth century. It causes blistering to the skin and mucous membrane with no specific antidote. Mustard gas damage cells through alkylation of DNA and through cytokine-mediated inflammatory response. The long term effects of the exposure to mustard gas are known to include damage to immune system, birth defects and lymphoma [Sulfur mustard is an alkylating compound with a potent vesicant property has been used as a chemical weapon in various conflicts during the 20lymphoma ,63. An alymphoma  and in slymphoma ,66, the lymphoma ,68. HoweIncendiary weapons have been issued to US forces in Iraq, apparently mainly to Marine Corps Aviation Wing against Iraqi troops during the 2003 invasion and in Fallujah assault in 2004 . White pBabies born in Fallujah are exhibiting high rates of mortality and birth defects. In September 2009, 170 children were born at Fallujah General Hospital, 24% of whom died within 7 days, 75% of those exhibited deformities including children born with two heads, no head, a single eye in their foreheads or missing limbs. The comparable data for August 2002 recorded 530 births of whom 6 died and only one of whom was deformed . EnvironMaternal nutritional factors have also been identified as an important contributor to neural tube defects ,73. MuchMaternal age is strongly associated with chromosomal anomalies and the rising proportion of older mothers is likely to contribute to increase in prevalence of anomalies ,81. StudRecently, it is assumed that the health effects of maternal stress may include increased risk of certain birth defects ,85. StreAs no enough data on pre 1991 Gulf War prevalence of birth defects in Iraq are available, the ranges of birth defects reported in the reviewed studies from Iraq most probably do not provide a clear indication of a possible environmental exposure including DU or other teratogenic agents although the country has faced several environmental challenges since 1980.CDD: Chorinated Dibenzo-p-dioxin; DU: Depleted Uranium; NTDs: Neural tube defects; PAHs: Polycyclic aromatic hydrocarbons.The authors declare that they have no competing interests.All authors contributed to the writing, revision and supportive literature reviews in the preparation of this manuscript. All authors read and approved the final manuscript.


Background. Hydatid cyst disease is a zoonosis caused by Echinococcus genera. The disease is endemic to certain rural areas in the world. Operative treatment is the main component in curing hydatid cysts of the liver. Objective. Describing the unique characteristics of the hydatid cyst patients in Israel, a nonendemic country. Methods. Data was collected form 29 patients treated operatively in Rabin Medical Center from 1994 to 2007. Results. The study included 18 females and 11 males with an average age of 54.9 years. Fifty-two% of the patients immigrated as children from Arab countries to Israel, 21% were Arab-Israelis leaving in the north and center of Israel, and 24% immigrated from the former Communist Bloc. Pericystectomy was performed in 20/29, and cyst unroofing was performed in 9/29. Hydatid cysts average size was 10.7 cm, and the cysts were located in the right or left or involved both lobes in 62%, 28%, and 10% of the lesions, respectively. Postoperative mortality occurred in one case, and severe morbidity occurred in 4 patients. Conclusions. Hydatid cyst disease in Israel is uncommon and is mostly seen in distinct 3 demographic groups. Despite the relatively low patient volume, good results in terms of morbidity, mortality, and recurrence were achieved. Echinococcus granulosus . The incidence of this disease is strongly correlated with certain geographic areas in the world. It is endemic to many rural areas where humans are in close contact with the different hosts in the complex life cycle of the parasite. Livestock  are the intermediate host, and small carnivores  are the definitive hosts. In humans, like in herbivores, the ingested eggs hatch, and then a hydatid cyst filled with larvae is formed. The larvae cannot develop into its adult form unless it is digested by a carnivore.Hydatid cyst disease is a zoonosis caused mainly by the cestode genus In 50%–70% of hydatid disease cases, the liver is involved . HydatidThe management of hydatid cyst of the liver usually relies on a surgical procedure as the main component of therapy , 4. The The aim of this study is to define the unique features of patients managed surgically for liver hydatid disease in Israel. Furthermore, by reviewing our surgical experience we intend to try and compare a pericystectomy with cyst unroofing.t-test.The computerized and paper archives of patients treated surgically for hepatic hydatid cyst were reviewed. All cases in Rabin Medical Center, a large tertiary referral center in Israel from 1994 to 2007, were included. Data were collected on patient's demographic characteristics, signs and symptoms on presentation, clinical and laboratory findings, management, outcome, and pathology findings. Hospital stay, operative blood transfused, severe morbidity, and cyst size for the two different surgical techniques were compared using a Student's Twenty-nine patients, 18 females and 11 males, underwent an operation for hepatic hydatid cyst in Rabin Medical Center from 1994 to 2007 . These immigrants arrived to Israel in the 1950s and 1960s when their average age was 12.4 years old (ranging from 1–20 years). Another group of patients was immigrants from Eastern European countries and the former Soviet Union  composing 21% of the study population. The third group of patients comprised 24% of the patients and was Israeli-Arabs from the north and center of Israel. Three of these patients were from a single town. All patients underwent abdominal ultrasound and/or CT scan prior to surgery.Sixty-nine percent (20/29) of the operations were pericystectomy where the entire hydatid cyst is excised and thirty-one percent (9/29) of the operations were unroofing of the cyst in which the cyst is decompressed  of operative mortality  was recorded. The patient underwent urgent operation due to sepsis subsequent to biliary invasion. The hydatid cyst was attached to the vena cava. During surgery, the patient suffered severe hemorrhage and died 7 days later. The rate of minor postoperative morbidity was 37.9%, and severe morbidity occurred in 13.8%. The later was composed of 2 cases of biliary leaks, one case of pneumothorax due to thoracic invasion, and one case of anaphylaxis due to cyst rupture.Antihelminthic medical therapy  was administered to all elective patients 3 months prior to surgery. No known recurrences of hydatid cyst were noted in our study population.This study included 29 patients that underwent surgery for liver hydatid cyst in Rabin Medical Center, Israel, during a 14-year period. To the best of our knowledge, this is the first report of hydatid cyst surgical series in Israel and only one of a small number of reports –13; howeJewish immigrants from Arab countries that arrived to Israel as children or young adults (average age 12.4 years). They had only few years of exposure at their country of birth with a period of few decades until appearance of symptoms and reaching a diagnosis of their hydatid disease. This group best demonstrates the lengthy and relatively nonvirulent natural course of uncomplicated hydatid disease as was previously described [Jewish immigrants from the former Communist countries. These patients arrived from communist countries mostly in the late 1980s and early 1990s. This group was characterized by different age groups and exposure periods prior to immigration to Israel.Israeli-Arabs from the central and northern parts of Israel. Usually known for its rural nature, in most cases this group has closer connections to nonindustrialized livestock farming. The patients in this group were relatively young at presentation. This may be due to more intense exposure.The demographic composition of the study population is interesting. It can be divided to 3 distinctive groups as follows.All of the patients in the study could be ascribed to one of the 3 demographic groups. By so, we describe here an important risk factor unique to hydatid cyst patients in Israel. This is a derivative of the unique sociodemographic structure in Israel.In this study, complete resection of the hydatid cyst was attempted by performing pericystectomy when it was technically possible. The favorable ratio between pericystectomy and unroofing performed in our study demonstrates this approach. In some cases of very large cysts and cysts adjacent to vascular or biliary structures or severe abdominal adhesions, pericystectomy could not be performed, and unroofing of the cyst was chosen. In cyst unroofing stringent precautions were taken to avoid intra-abdominal spillage of the cyst content and attention was directed to meticulous scraping of the entire germinal layer.Many authors in the recent literature agree that radical resection of the hydatid cyst should be preferred when feasible –17, althThe mild complication rate was 37.9% and consisted mainly of postoperative mild anemia, uncomplicated fever, and atelectasis. The severe complication rate was 13.8%. We had one case of post surgical mortality. These complication rates are comparable or slightly higher than results of medical centers in endemic countries with higher volume of hydatid cysts , 20, 21.The relatively small population size in our study is a double-edged sword. On one hand, it limits the ability to reach statistically based conclusions, but, on the other, it holds the key in describing the features of hydatid disease in a nonendemic area. Another possible limitation of this study is a lack of adequate long-term followup due to relatively short surgical followup. To the best of our knowledge no hydatid recurrences occurred. It can be safely assumed that the report rate on recurrence is close to 100%.In conclusion, hydatid cyst disease in Israel is infrequent. Patients most likely belong to one of 3 demographic groups: immigrants from Arab countries, the former Communist countries, or Israeli-Arabs. The preferred surgical technique is cyst pericystectomy when possible. Surgical treatment is undoubtedly reasonable in terms of morbidity, recurrence, and mortality.


The electrical modulation properties of the output intensity of two-photon absorption (TPA) pumping were analyzed in this paper. The frequency dispersion dependence of TPA and the electric field dependence of TPA were calculated using Wherrett theory model and Garcia theory model, respectively. Both predicted a dramatic variation of TPA coefficient which was attributed into the increasing of the transition rate. The output intensity of the laser pulse propagation in the pn junction device was calculated by using function-transfer method. It shows that the output intensity increases nonlinearly with increasing intensity of incident light and eventually reaches saturation. The output saturation intensity depends on the electric field strength; the greater the electric field, the smaller the output intensity. Consequently, the clamped saturation intensity can be controlled by the electric field. The prior advantage of electrical modulation is that the TPA can be varied extremely continuously, thus adjusting the output intensity in a wide range. This large change provides a manipulate method to control steady output intensity of TPA by adjusting electric field. Two-photon absorption (TPA) is a third-order nonlinear absorption process which is closely related to the imaginary part of nonlinear susceptibility of the material . BecauseIn this paper, the dispersion dependence of TPA on photon frequency is calculated using second-order perturbation theory. Then, the electric field modulation effect of two-photon absorption coefficient (TPAC) in HgCdTe photodiode is simulated from a two-band model. The results show that the TPAC in space charge region (SCR) is enhanced dramatically by the build-in electric field. A TPA Franz-Keldysh Effect (FKE) mentioned by Garcia is adapted to interpret this phenomenon. On this basis, the dependence of output intensity on electric field is calculated using the TPA modulation relationship. It shows that the output intensity can be manipulated continuously by adjusting the bias voltage.i〉 to a final state |f〉 involving simultaneous absorption of two photons was theoretically predicted by Göppert-Mayer −1 and p represents ε · p. Retaining the matrix element corresponding to the direct contribution, TPAC can be expressed asc, q, Eg and ℏω are speed of sound, electron charge, energy gap, and incident photon energy, respectively. P ∝ pcvℏ/m is Kane momentum parameters. f is defined as the numerical factor. Equation , mc, mv, and mu are interband momentum matrix element, electric field, Airy function, effective mass of electron and hole, and the reduced mass, respectively. In the whole excitation process, principle of energy conservation is satisfied by δ function, while momentum conservation is satisfied by Δk = kc − kv = 0; thus the TPAC can be derived asς0 = (2ℏω − Eg)/Eμ, Eμ = (ℏ2e2F2/2mμ)1/3, is the characteristic energy of the dc electric field. Because of the introduction of this parameter, the TPAC will change with the electric field strength. Ep is the transition matrix. K = 1940 cm/GW (eV) is a material-independent constant.A two-band model consisting of heavy-hole and light-hole bands mentioned by Garcia  is used F < 30 kV/cm. However, if the electric field F > 30 kV/cm, the calculation data still increase, while the experimental TPAC shows saturation. This can be attributed to the saturation of the electric field in the pn junction in this range, and the electric field strength in the SCR will not increase anymore.Using the expression in , the TPAβ1 = 10.5 cm/MW) has been enhanced by about seven times comparing to zero electric field (β0 = 1.5 cm/MW). When the built-in electric field varies from 13.4 kV/cm to 30 kV/cm, TPAC will be enhanced into 198 cm/MW, about 19 times increasing. This significant enhancement is attributed to the FEK of the TPAC in SCR. The absorption coefficient increased in the strong electric field of SCR by increasing the coupling intensity of electron and hole wave functions. FKE occurs because the electric field assisted tunneling process in SCR makes the effective energy gap shrink for an electron in the interband transition. The band gap shrinkage is proportional to the electric field [Eg ~ F. Consequently, the electrons exited from valance band have more probability to transmit into the conduction band. This mechanism has made the TPAC within the SCR increase [increase , 14.x is the cell thickness of absorption layer and In is the incident intensity of n layer. As a result of back-illuminated, the incident light passes through the flat band of p region first and then into the SCR. Comparing with the thick base region, the thickness of the heavy doped emitter can be neglected. Therefore, only the optical loss in flat belt layer and SCR is considered here. Using the conclusion of TPAC modulation mentioned above, the effects of TPAC manipulation on the output intensity can be simulated, which is shown in Based on the analysis given above, it can be known that the TPAC can be adjusted effectively by varying the electric field applied, thus changing the output light intensity. Undoubtedly, this TPAC manipulating effect is very attractive for the nonlinear optical devices such as optical limiter. In the following, we will simulate the effects of TPAC manipulation on the output intensity. The output intensity of pn junction can be solved using function-transfer method :(7)In+1It can be seen from In conclusion, we calculated the dependence of electric field on the TPAC and the output intensity in pn junction photodiode. Because of the TPA FKE, the TPAC could be manipulated by adjusting the electric field within the SCR. We simulated the dependence of electric field strength on the output intensity. It shows that the clamped saturation intensity can be controlled by the electric field. From the analysis of nonlinear TPA in the semiconductor, one can obtain a method to control steady output intensity of TPA pumping by adjusting electric field or bias voltage. Since the TPA is an important mechanism in semiconductors, our initial result on the electric field induced tunability of TPA, and its influence on the output intensity would can be very useful for the nonlinear optical device.


A 36-year-old woman presented with a cystic lesion located on the right popliteal fossa, which grew slowly for 7 years and became remarkably larger in the last few months. The lesion was dark red in color Fig  and elasWhat is the differential diagnosis of a subcutaneous cyst around the knee?Which diagnostic imaging studies are appropriate to help reach diagnosis?What are the therapeutic options for this lesion?,The differential diagnosis of a lesion presenting as a subcutaneous cyst includes the following benign entities: epidermoid cyst, calcifying epithelioma, venous malformation, lymphatic malformation, hemangioma, ganglion, and abscess. Especially, Baker's cyst, known as a popliteal cyst, is frequently seen in the popliteal area, reportedly in 10% to 41% of MR (magnetic resonance) examinations of the knee.3In biopsy planning, care must be taken not to jeopardize subsequent treatment. There should be no rising of flaps for wound closure, or contamination of surrounding tissues with tumor cells.,14Diagnostic imaging studies of DFSP have not been established, but MRI11


Background: Industrial spills of volatile organic compounds (VOCs) in Endicott, New York (USA), have led to contamination of groundwater, soil, and soil gas. Previous studies have reported an increase in adverse birth outcomes among women exposed to VOCs in drinking water.Objective: We investigated the prevalence of adverse birth outcomes among mothers exposed to trichloroethylene (TCE) and tetrachloroethylene [or perchloroethylene (PCE)] in indoor air contaminated through soil vapor intrusion.Methods: We examined low birth weight (LBW), preterm birth, fetal growth restriction, and birth defects among births to women in Endicott who were exposed to VOCs, compared with births statewide. We used Poisson regression to analyze births and malformations to estimate the association between maternal exposure to VOCs adjusting for sex, mother’s age, race, education, parity, and prenatal care. Two exposure areas were identified based on environmental sampling data: one area was primarily contaminated with TCE, and the other with PCE.n = 76], small for gestational age , term LBW , cardiac defects , and conotruncal defects . In the PCE-contaminated area, RRs for cardiac defects (five births) were elevated but not significantly. Residual socioeconomic confounding may have contributed to elevations of LBW outcomes.Results: In the TCE-contaminated area, adjusted rate ratios (RRs) were significantly elevated for LBW [RR = 1.36; 95% confidence interval (CI): 1.07, 1.73; Conclusions: Maternal residence in both areas was associated with cardiac defects. Residence in the TCE area, but not the PCE area, was associated with LBW and fetal growth restriction. After a 1979 spill of 4,100 gallons of 1,1,1-trichloroethane (TCA) at a large IBM semiconductor manufacturing facility in the Village of Endicott, New York, groundwater sampling conducted in 1980 revealed the presence of a mixture of contaminants beneath the site and nearby residential and commercial areas. Groundwater sampling identified a larger than expected plume of contaminants, including trichloroethylene (TCE) and tetrachloroethylene [perchloroethylene (PCE)], along with lesser amounts of TCA, dichloroethane, dichloroethene, methylene chloride, vinyl chloride, freon 113, and other volatile organic compounds (VOCs), with total groundwater VOC concentrations ranging from 5 to > 500 µg/L [New York State Department of Environmental Conservation (NYSDEC) 2003]. Although the TCA spill initiated the extensive groundwater sampling, the other contaminants discovered were the result of prior spills and releases. The contaminant plume extended from the 135-acre facility southward beneath approximately 70 blocks of the Village of Endicott, a community of 13,000 located in upstate New York. The groundwater has been treated and monitored since then.Until recently, environmental scientists generally assumed that VOC-contaminated groundwater near hazardous waste sites resulted in potentially harmful exposures to VOCs only if the groundwater was used as a drinking water source. Because the residential drinking water in Endicott is supplied primarily from wells outside the plume area, it was assumed that residents were not being significantly exposed to contaminants from the plume. Beginning in the late 1990s, new information emerged showing that contaminants volatilized and moved through air pockets in soil into structures above or near contaminant plumes through a process known as soil vapor intrusion (SVI) [New York State Department of Health (NYSDOH) 2006].3 (3. In the area with the highest off-site contaminant levels (the core area), the median indoor air level of TCE was 16 µg/m3 . Data compiled from 15 U.S. indoor air studies that measured background concentrations of VOCs in homes not expected to be influenced by SVI show median background indoor air concentrations for TCE ranging from the reference limit to 1.1 µg/m3, with the 95th percentile ranging from 0.6 to 3.3 µg/m3 [U.S. Environmental Protection Agency (EPA) 2011]; 81% of the indoor air levels in the core area in Endicott were > 0.6 µg/m3, and 67% were > 3.3 µg/m3, the lower and upper 95th percentile range values (NYSDEC 2003). A second, smaller area of contamination was also found where PCE predominated. PCE levels in this area ranged from 0.1 to 24 µg/m3 in indoor air, whereas median background U.S. indoor air concentrations for PCE have ranged from the reference limit to 2.2 µg/m3, and the 95th percentile ranged from 4.1 to 9.5 µg/m3 (U.S. EPA 2011). Duration of exposures before the discovery of SVI is unknown, but exposures through this pathway may date back at least to the 1970s. To reduce exposures, mitigation systems were installed in > 450 structures beginning in 2002.In 2000–2001, concerns about SVI in Endicott led to expanded off-site soil vapor sampling. TCE was the predominant contaminant in soil vapor, with relatively small fractions of TCA and PCE. Levels of TCE in soil vapor above the plume typically ranged from 100 to 10,000 µg/mAlthough there are numerous studies on the carcinogenicity of TCE and PCE, relatively few studies have looked at reproductive and developmental health outcomes associated with these chemicals. Previous studies of women living in areas with TCE- or PCE-contaminated drinking water have suggested an association between TCE exposure, and cardiac defects, oral clefts, neural tube defects (NTDs), and choanal atresia [Studies of women exposed to TCE-contaminated drinking water have shown some evidence of increases in low birth weight (LBW) or very LBW, term LBW, and small for gestational age (SGA) births [Agency for Toxic Substances and Disease Registry (ATSDR) 1998; In this report, we present the findings from an exploratory community study of adverse birth outcomes among residents living in an area with SVI by TCE and PCE. The Endicott SVI exposure area is one of the earliest such sites to be identified and the largest site in New York State to receive this type of health outcome investigation.Study design. We compared birth outcomes among residents of the exposed community and birth outcomes in the general New York State population using multivariate Poisson regression analyses. Existing birth certificate and birth defect registry records were used to obtain information on outcomes and maternal and child risk factors at the individual level, and exposure was classified at the group level.The study was reviewed and approved by the NYSDOH Institutional Review Board, which waived informed consent because the study was of no or minimal risk to the subjects and could not be practicably carried out without a waiver.Study population. The study population included all live births in the Endicott study area, and the comparison population included all births in the rest of New York State, excluding New York City. LBW, preterm, and fetal growth restriction outcomes were studied for singleton births from 1978 to 2002; birth defects were studied for all births from 1983 to 2000. These years were chosen to most closely match the exposure years for which birth outcome data were available.Birth certificate data from New York State Vital Statistics files  were used to examine LBW, preterm births, and fetal growth restriction among singleton births. The birth weight and preterm outcomes are defined as follows: LBW , very LBW , preterm birth (< 37 weeks gestation), and very preterm birth (< 32 weeks gestation). The growth restriction outcomes are term LBW  and SGA. SGA is defined as a birth weight below the 10th percentile of the New York State (excluding New York City) birth weight distribution of singleton births stratified by gestational week, sex, and 5-year time period (1978–1982 through 1998–2002) .Birth records with missing birth weight or birth weight < 100 g or > 8,000 g were excluded from the birth weight analyses (0.3% of the birth records). Records missing gestational age or with gestational ages < 12 weeks or > 50 weeks were excluded from the preterm analyses (3.2% of the birth records). For the SGA and term LBW analyses, exclusions for implausible birth weight/gestational age combinations follow those of International Classification for Diseases, 9th Revision (ICD-9) . The CMR linked the birth defect records to their corresponding birth certificate record to obtain information on residence at birth and maternal and infant characteristics. Defects were grouped into two broad categories: all reportable birth defects, and a subset of all reportable birth defects called “surveillance birth defects.” Reportable birth defects include all major birth defects required to be reported to the CMR (NYSDOH 2004). Surveillance birth defects, which account for about half of all reportable birth defects, include about 80 types of birth defects that are easily recognizable and consistently and accurately diagnosed by physicians  . Specific birth defects were identified using codes from the ysicians . In addiExposure assessment. Approximately 25% of structures in the area potentially affected by SVI were sampled for indoor air VOC levels. Structures near the periphery were oversampled because the sampling’s primary purpose was to identify a boundary beyond which there were no discernible impacts on indoor air, for mitigation purposes. For this reason, we could not assign exposures at the household level or assign exposure gradients. Because of differences in the predominant contaminants, two exposure areas were identified: a primary exposure area located south of the IBM facility (the TCE area) and a smaller, contiguous area, to the west (the PCE area) .3 to > 10,000 µg/m3 (NYSDEC 2003).The TCE and PCE area boundaries were drawn using village block boundaries that generally captured the population of the area where mitigation systems were offered. This was accomplished by overlaying a digital map of the 2000 U.S. Census blocks (U.S. Census Bureau 2000) on the areas of contamination using a geographic information system . Because the census blocks in Endicott are relatively small, the study area boundaries closely coincided with the area where the inferred VOC presence in soil gas ranged from 10 µg/mExposure status was assigned at the group level based on residence within the TCE or PCE areas. We used the mother’s residential address at the time of birth to assign births to the study areas. Addresses were geocoded to a latitude and longitude using Mapmarker Plus . If an address was not automatically geocoded, it was manually assigned a latitude and longitude using tax parcel data , NYS New York State digital street files , ZIP+4 files , and street-by-street ZIP code directories . Thus, a birth was considered exposed if the mother resided in one of the study areas at the time of birth, and the general population of New York State (excluding New York City) residing outside of the study areas was considered unexposed.Statistical analysis. We used Poisson regression to analyze the relationship between exposure status and adverse birth outcomes. Data on potential confounders (factors most frequently associated with birth outcomes) were obtained from the birth certificate records. The following covariates were included: mother’s age , education , race , infant’s sex, number of previous live births , and adequate prenatal care  .al care) . SeparatBecause smoking is a major risk factor for several of these outcomes, we conducted a subanalysis of LBW and fetal growth restriction that included an additional term for smoking status , as reported by the mother on the birth certificate. Although this information has been collected since 1988, we limited this subanalysis to 1998–2002 (5 years) because these smoking data are more complete.Table 1 presents the demographic characteristics of the Endicott study areas and New York State (excluding New York City) for 1980 and 2000. The population of the TCE area accounts for about 80% of the population of the combined study area. Between 1980 and 2000, the population of the combined study area declined 15%, whereas the New York State population increased about 5%. The combined study area had a lower percentage of minorities than the rest of the state. Although the statewide percentage of households living below the poverty level remained steady from 1980 to 2000, at about 10%, it increased from 12% to 24% in the study area. In addition, the median household income in the study area fell from two-thirds of the statewide median in 1980 to half of the statewide median in 2000. The demographic characteristics of the TCE and PCE areas were similar (data not shown).Geocoding identified 1,440 live births to mothers living within the combined study area during 1978–2002. There were 1,090 births in the TCE area and 350 births in the PCE area. The remaining 3.6 million births from 1978 through 2002 in New York State (excluding New York City) were assigned to the comparison population. Because of the small number of births in the study area, there were very few exposed cases of some of the rarer outcomes. This was more apparent in the PCE area, where only one exposed case each of conotruncal defects, very preterm births, and very LBW births were observed. Term LBW in the PCE area and several categories of heart defects in both areas had fewer than 10 exposed cases. The number of exposed cases of each outcome is given with the results in Tables 2 and 3. Results based on small numbers should be interpreted cautiously.RR estimates for the covariates included in the models for LBW, SGA, term LBW, and surveillance, major cardiac, and conotruncal birth defects are shown in Table 4 for the TCE area. LBW, SGA, and term LBW were associated with maternal age > 35 years, lower education, nonwhite race, no previous births, inadequate prenatal care, and infant female sex. Surveillance defects and cardiac birth defects were associated with maternal age > 35 years, lower education, and infant male sex. In addition, cardiac defects were associated with nonwhite race and previous live births; however, these factors were inversely associated with surveillance birth defects. Adequate prenatal care was inversely associated with major cardiac defects.n = 76), SGA , and term LBW . Very LBW was also elevated in the TCE area, although not significantly so . In the combined study area the RRs were significantly elevated for SGA and term LBW, a reflection of the results for the TCE area.The results from the Poisson regressions of birth weight, prematurity, and growth restriction outcomes are presented in Table 2. In the PCE area, none of the adjusted RRs were statistically significant, and all had RRs < 1.0 with the exception of SGA, which had an RR of 1.04. Very LBW, term LBW, and very preterm all had fewer than five cases, as noted above; thus, these results should be interpreted with caution. In the TCE area, significantly elevated RRs were seen for LBW , SGA (n = 35), and term LBW (n = 11), and the association increased with the number of cigarettes smoked for each outcome (data not shown). With smoking status included in the models, RRs decreased for all outcomes: for LBW, from 1.60  to 1.37 ; for SGA, from 1.54  to 1.31 ; and for term LBW, from 2.56  to 2.08 .During 1998–2002, 39% of mothers in the study areas and 14% of mothers statewide reported smoking during the pregnancy. In the combined study area smoking was significantly associated with LBW (n = 10) and TCE areas (n = 25), with a statistically significant elevation for the combined study area . Cardiac birth defects were increased in both areas, with RRs increasing from the most general grouping  to most specific . In the TCE area, all cardiac defects were significantly elevated , whereas the major cardiac defects (n = 6) were of borderline statistical significance . In the combined study area, similar significant elevations were seen for all three groupings of cardiac defects. The highest RRs were for conotruncal defects and were statistically significant in the TCE area  and the combined study area . Although statistically significant, these RRs were based on three and four exposed cases, respectively.Between 1983 and 2000, 61 children born in the combined study area  were diagnosed with at least one reportable birth defect (Table 3). There were no reported cases of NTDs, orofacial clefts, or choanal atresia in the TCE or PCE areas over the 18-year study period. All reportable, surveillance, and cardiac birth defect groupings showed elevated RRs for both areas combined (Table 3). Surveillance birth defects were increased in the PCE  (ATSDR 1998). Researchers evaluated 31 births with “long-term” TCE exposure and 141 births with “short-term” TCE exposure and reported an association between SGA among male infants and “long-term” TCE exposure . In Woburn, Massachusetts, a retrospective cohort study found that the prevalence of SGA among 2,211 births was significantly elevated among mothers who had been exposed to drinking water contaminated with TCE (267 ppb) and PCE (21 ppb) during the third trimester of pregnancy .Similar to our study, Surveillance birth defects and cardiac birth defects were elevated in both the PCE and TCE areas. Although similar in magnitude, the elevations were statistically significant only in the more populated TCE area. RRs for all cardiac defects and major cardiac defects for the PCE and TCE areas suggest an approximate doubling in the prevalence of these defects. When we limited the analysis to the more etiologically homogeneous group of conotruncal defects, the RRs suggest nearly five times greater prevalence of these defects in both the PCE and TCE areas. However, estimates were based on only four exposed cases, and CIs were wide. Animal studies suggest that TCE and its metabolites are specific cardiac teratogens ; howeverSeveral epidemiological studies have reported an excess prevalence of cardiac defects in communities exposed to TCE-contaminated drinking water. 3 and in indoor air of 5.6 µg/m3. Based on these concentrations, applied to a “standard” adult male, their model resulted in a total daily absorbed TCE dose of 292.0 µg/day, of which 51% was from ingestion, 14% from indoor air inhalation, 22% from shower inhalation, and 12% from shower dermal absorption. Neither TCE nor PCE has ever been detected in public water in Endicott at levels exceeding federal or New York State standards of 5 µg/L. . Thus, although the Endicott exposures did not include ingestion, the Endicott and comparison studies all include inhalation exposures.Although most published studies involved communities exposed to contaminated drinking water, the route of exposure in Endicott was inhalation from SVI. The different exposure pathways create a challenge for comparing exposure levels across studies. Inhalation exposures from contaminated water, during showering, for example, may result in similar levels of exposures as from ingestion. Strengths and limitations. An important strength of our study was the use of available environmental and health outcome data. This approach allowed the study to be completed relatively quickly and inexpensively. Another strength is the use of statewide, individual-level birth data from the CMR and New York State Vital Statistics records. These data are gathered consistently for the entire state, are managed in centralized databases, and provide population-based data for births. Individual-level information on birth certificates enabled analytic control for other risk factors, including the sex of the baby; maternal age, race, and education; parity; and adequacy of prenatal care. In addition, the use of a large population (New York State excluding New York City) as a comparison population provides sufficient power to detect small associations between exposure and outcome.A major limitation of this study, and most of the studies we cite, is that exposure at the individual level could not be measured and is largely unknown. The exposure assessment for the present study was based on soil vapor and indoor air sampling, which were used to determine the exposure areas. Although the study looked at births as far back as 25 years, indoor air sampling data was done between 2001 and 2004. However, not every house in the area was sampled, levels varied from house to house, and the amount of time spent in the house is unknown. In addition, some of the mothers may also have been employed by manufacturers in Endicott that used VOCs. If there were other VOC exposures in the community, the risks of adverse health outcomes associated with SVI in the residence would have been overestimated.Exposure misclassification could have occurred from relying on the mother’s address on the birth certificate. Studies have estimated that 22–32% of women may move between the time of conception and delivery . The stuAnother limitation of the study was the small number of births in the study area and, consequently, a small number of cases for rarer outcomes. This was especially problematic in the PCE area, where nearly half of the outcomes had < 10 cases. However, even the larger TCE area had < 10 cases of some of the cardiac defect subcategories. This led to wide CIs around the RRs for some outcomes, and therefore, the results should be interpreted with caution.The inability to adequately control for smoking is also a limitation for certain outcomes evaluated in this study. Cigarette smoking is the most important risk factor for fetal growth restriction . The EndAnother limitation is that the population of the study area is of lower socioeconomic status (SES) than the general comparison area population. Several of the outcomes are associated with lower SES, specifically LBW, term LBW, and SGA. We included mother’s education in the model to attempt to control for SES differences. Education was inversely associated with all of the birth outcomes. We included adequacy of prenatal care in the model because access to health care may be one of the pathways through which SES affects these birth outcomes. Although we used individual-level information for these important risk factors, the statistical modeling was not able to completely control for factors related to SES that are substantially different in the exposed versus the comparison population. An additional concern was that inclusion of race in the models, given its correlation with SES, could artificially inflate the exposure RRs for the predominantly white exposed population. Analyses that excluded race as a variable did show some slightly reduced RRs but did not affect the study’s overall results (data not shown). It is possible, however, that the models do not fully control for SES differences. Residual confounding by SES would lead to inflated estimates of risk associated with living in the Endicott study areas.The study’s strongest finding is for an association of TCE and PCE exposures with cardiac birth defects, although some subgroups were based on a small number of cases. We found that the effects of education and prenatal care levels were greater on LBW and growth restriction outcomes than on birth defects. This is consistent with the interpretation that the birth defect findings are less likely to be artifacts of confounding by SES than are LBW and growth restriction. If the models controlled adequately for SES differences, as well as other biases, then living in the Endicott area is associated with increases for both types of adverse birth outcomes. The findings from the analyses that controlled for smoking were consistent with this interpretation; it showed a statistically significant elevation for term LBW, suggesting that smoking among women in the Endicott (a behavior associated with lower SES) could not fully account for the elevation of term LBW.This study is one of the first to examine a community with TCE and/or PCE exposure primarily through SVI. SVI is often discovered long after groundwater contamination begins, which makes historic exposure levels difficult to assess. This study adds to the larger body of evidence linking TCE, and possibly PCE, to adverse birth outcomes. We observed increased LBW, term LBW, and SGA among mothers living in the TCE area but not in the PCE area. We observed an increased prevalence of cardiac defects and, specifically, for conotruncal cardiac defects in the TCE and PCE areas; however, the latter result was based on just four cases. Nonetheless, this exploratory study suggests that additional research on exposures to VOCs and birth outcomes, particularly cardiac defects, is needed.


Recent studies have demonstrated that low and high birth-weight at birth are risk factors of developing diabetes. The aim of this study was to determine if the abnormal birth-weight is related with hyperinsulinemia and elevated index of the Homeostasis Model assessment for Insulin Resistance (HOMA-IR) at birth, in at term newborns.Newborns with gestational age between 38 and 41 weeks, products of normal pregnancies of healthy mothers aged 18 to 39 years, were eligible to participate. Small-for-gestational age (SGA) and large-for-gestational age (LGA) newborns were compared with appropriate-for-gestational (AGA) age newborns. Incomplete or unclear data about mother’s health status, diabetes, gestational diabetes, history of gestational diabetes, hypertension, pre-eclampsia, eclampsia, and other conditions that affect glucose metabolism were exclusion criteria. Hyperinsulinemia was defined by serum insulin levels ≥13.0 μU/mL and IR by HOMA-IR ≥2.60. Multiple logistic regression analysis was used to determine the odds ratio (OR) that computes the association between birth-weight (independent variable) with hyperinsulinemia and HOMA-IR index (dependent variables).p=0.03), whereas IR in 3 (23.1%), 8 (36.4%), and 10 (13.9%) newborns with SGA, LGA and AGA (p=0.06). The LGA showed a strong association with hyperinsulinemia  and HOMA-IR ; although without statistical significance, the SGA showed a tendency of association with hyperinsulinemia  and HOMA-IR .A total of 107 newborns were enrolled; 13, 22, and 72 with SGA, LGA, and AGA, respectively. Hyperinsulinemia was identified in 2 (15.4%), 6 (27.3%), and 5 (6.9%) with SGA, LGA, and AGA (Our results suggest that LGA is associated with hyperinsulinemia and elevated HOMA-IR at birth whereas the SGA show a tendency of association. The type 2 diabetes is a complex disease characterized by decrease of insulin sensitivity and impaired insulin secretion . Recent In addition to genetic predisposition, nutritional, and environmental factors, it has been reported that the elevated levels of cytokines increase glucocorticoid activity and decrease serum adiponectin during pregnancy, which affects birth-weight -11. FurtIt has been described that in large-for-gestational age (LGA) infants, cord serum levels of leptin are strongly related with birth-weight and insulin levels, suggesting that part of insulin’s effect on birth-weight is mediated by leptin . FurtherGiven that studies about association between birth-weight and insulin resistance has been developed measuring insulin and glucose levels in adolescence or adulthood and collecting information of birth-weight in a retrospective way, the aim of this study was to determine if the abnormal birth-weight is related with elevated insulin levels and increase of the Homeostasis Model assessment for Insulin Resistance (HOMA-IR) index at birth, in at term newborns.With protocol approval by the Mexican Social Security Institute Research Committee and after obtain the mother’s informed consent, a cross-sectional study of two phases was carried out.In the first phase, with the purpose of establish the cutoff point of HOMA-IR at birth in appropriate-for-gestational age (AGA) newborns delivered at term, a total of 150 newborns with birth-weight greater than 2500 g and lower that 4000 g, were enrolled in a cross-sectional non-comparative study.In the second phase, an independent sample of 107 newborns were enrolled in a cross-sectional comparative study to determine if LGA or small-for-gestational age (SGA) is related with hyperinsulinemia and elevated HOMA-IR in newborns delivered at term.In both phases, eligible participants were newborns of mother’s aged 18 to 39 years and gestational age (determined by ultrasound) between 38 and 41 weeks. All newborns were of pregnant women without diagnosis of diabetes or gestational diabetes , history of gestational diabetes, high blood pressure, pre-eclampsia, eclampsia, asthma, epilepsy, or malnutrition.In addition, in both phases the presence of congenital malformations, incomplete or unclear data about mother’s health status as well as preterm delivery, intrauterine infection, smoking or alcohol consumption during pregnancy, and the use of dextrose solutions during labor, or drugs that affect the glucose metabolism, were exclusion criteria.In the second phase of the study, in order to control potential confounders related with maternal characteristics, the groups were matched by mother’s age, parity, and gestational age.Anthropometric characteristics and blood samples were obtained by pediatricians at delivery room, immediately after delivery. Blood samples were collected from the umbilical cord vein.Newborns were distributed in the groups in study according the presence of SGA, AGA, or LGA.Detailed information regards mother’s health was collected by direct medical history, physical examination, and by reviewing their medical records of prenatal control.The body mass index (BMI) of mothers before pregnancy was calculated as the weight (kilograms) divided by the height (meters) squared. The height and weight were assessed with a stadiometer using a fixed scale. The increments of the weight and height measurements were 0.1 kg and 0.01 m, respectively.SGA, AGA, and LGA were defined by weight at birth <2500g, ≥2500<4000g, and >4,000g, respectively ,19.The HOMA-IR index was calculated using the formula: fasting insulin (μU/mL) x fasting glucose (mmol/L)/22.5 .Serum glucose was measured using the glucose-oxidase method . The intra- and inter-assay coefficients of variation for glucose measurements were 2.1 and 2.8%. Insulin levels were measured by microparticle enzyme immunoassay , with intra- and inter-assay variation coefficients of 4.1% and 6.2%.n was calculated to normalize skewed data.Differences between the groups were estimated using one-way ANOVA with post hoc Bonferroni test. The LogMultiple regression logistic analysis adjusted by maternal weight before pregnancy and sex of newborn was used to determine the odds ratio (OR) that computes the association between birth-weight (independent variable) with hyperinsulinemia and HOMA-IR index (dependent variables).P value <0.05 defined statistical significance. Data were analyzed using the statistical package SPSS 15.0 .The 95% confidence intervals (CI 95%) were determined, and a The characteristics of the mothers and newborns enrolled in the first phase of the study are shown in Table th percentile of distribution for insulin levels was 13.0 μU/mL and the fourth quartile of HOMA-IR index 2.60. In the absence of cutoff points for insulin levels and HOMA-IR index in the newborn at term, these values were considered as the cutoff points for the second phase of the study.Distributions of insulin, glucose, and HOMA-IR at birth of AGA newborns are shown in Table In the second phase of the study, 13 (12.1%), 22 (20.6%), and 72 (67.3%) newborns delivered at term were enrolled in the SGA, LGA, and AGA groups, respectively.Clinical and biochemical characteristics of the mothers and newborns in the second phase of the study are shown in Table The mother’s weight and BMI before pregnancy was significantly lower in the mothers of SGA newborns as compared with mother’s of LGA and AGA newborns. The insulin levels in the newborns were significantly higher in the LGA group as compared with the SGA and AGA groups. Other variables showed no significant differences between the groups in study.p=0.03).Hyperinsulinemia was identified in 13 (12.1%) newborns: 2 (15.4%), 5 (6.9%), and 6 (27.3%) in the groups with SGA, AGA, and LGA (p=0.063).Elevated HOMA-IR was detected in 21 (19.6%) newborns: 3 (23.1%), 10 (13.9%), and 8 (36.4%) in the groups SGA, AGA, and LGA  and HOMA-IR ; the SGA showed a tendency of association with hyperinsulinemia  and HOMA-IR .Results of this study suggest that at LGA newborns have higher insulin levels and HOMA-IR than AGA and SGA newborns.It has been suggested that the association between LGA and insulin resistance may reflect the influence of several factors like maternal diabetes and gestational age -24; in tOur results agree with the report by Wolf et al.  who founFurthermore, in our study the sequence by weight class in the newborn at birth, for glucose and HOMA-IR was LGA<AGA<SGA and AGA<LGA<SGA, respectively, suggesting that LGA newborns at birth exhibited a decrease of insulin sensitivity, that requires an elevated compensatory insulin secretion from fetus to maintain euglycemia.Recently, Catalano et al.  conducteInterestingly, although SGA and AGA newborns exhibited similar HOMA-IR, blood cord glucose levels were higher in the SGA newborns, suggesting that could be an impaired insulin secretion and or insulin action related with the low birth-weight at birth. Additional factors related with the insulin production by fetus, such as elevated leptin and decreased adiponectin levels also could explain the findings of our study in regards SGA newborns. Further studies with the appropriate biochemical measurements are needed.Recently, in the Hyperglycemia and Adverse Pregnancy Outcome Study, it has been reported that cord serum C-peptide levels are strongly related with percent body fat of newborns and mothers glycemia ; althougIn regards the association between birth-weight and insulin resistance later in life, children and young adults with history of very low birth-weight and preterm delivery exhibit higher indices of HOMA-IR as compared with newborns delivered at term -29; giveAn additional contribution of our study was the reference values of cord insulin levels and HOMA-IR in AGA newborns. On this regard, because there are not reference values of insulin and HOMA-IR at birth, we evaluate its distribution in an independent group of AGA newborns who had the same inclusion and exclusion criteria that newborns enrolled in the second phase of this study. In this way, we obtained the percentile distribution of insulin levels and HOMA-IR as reference value of both variables.Finally, it is necessary to keep in mind that mechanisms involved in the relationship between fetal growth and insulin resistance have not been established with certainty; therefore, further studies in the field are necessaries.Several limitations deserve to be mentioned. First, the small sample size of LGA or SGA newborns in this study could be a source of bias that affects our conclusion. However, given the inclusion and exclusion criteria of this study, is unlikely to find newborns at term with LGA or SGA; further research that includes multiple centers is necessary to increase the sample size in order to confirm our results. Second, the cause-effect relationship cannot be established with certainty in the cross-sectional design studies; however, other methodological designs could involve ethical issues.The homogeneous target population and the strict matching criteria for controlling the main confounders were the main strengths of this study. In addition, given that pregnant women were in prenatal control, we have reliable data about maternal characteristics.In conclusion, our results suggest that LGA is associated with hyperinsulinemia and elevated HOMA-IR at birth whereas SGA show a tendency of association.The authors have not conflict of interest and nothing to disclose.LE. S-M, AC-C, MR-M, and FG-R had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analyses. Study concept and design: LE. S-M, FG-R, MR-M. Acquisition of data: AC-C, MR-M. Analysis and interpretation of data: LE S-M and FG-R. Drafting of the manuscript: LE. S-M. Critical revision of the manuscript for important intellectual content: MR-M, and FG-R. Statistical analysis: LE. S-M. Obtained funding: MR-M and FG-R. Administrative, technical, and material support: AC-C. Study supervision: MR-M. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2431/12/94/prepub


To ensure reliability, the sensor is calibrated in vivo using the ionophore nigericin and standard buffer solutions to equilibrate the external [H+]concentration with that of the cell compartments. This review highlights the nanosensors, ability to traffic and respond to pH of receptor-bound nanosensors (1) at physiological temperature (37°C)versus room temperature (25°C), (2) after pharmacological treatment with bafilomycin, an H+ ATPase pump inhibitor, or amiloride, an inhibitor of Na+/H+ exchange, and (3) in response to both temperature and pharmacological treatment. Whole-cell, time lapse images are demonstrated to show the ability to transform live cells into dynamic laboratories to monitor temporal and spatial endosomal pH. The versatility of these probes shows promise for future applications relevant to intracellular trafficking and intelligent drug design.This review captures the use of live cells as dynamic microlaboratories through implementation of labeled nanoparticles (nanosensors) that have both sensing and targeting functions. The addition of 2,4- It is kve cells . Measurein vitro . Fortunathe cell . To obtaμm can occur over the time course of a given experiment. However, it is noted that these nanoparticles have been or are about to be internalized because free-floating particles move too quickly to provide significant signal during the integrated acquisition time of the experiment. Time-lapse, hyperspectral SERS imagery showing the evolution of targeted nanosensor delivery into the cells at 25°C is shown in Y axis. There is most likely not a one-to-one correspondence between pixels measured and particles internalized. The measured size of each pixel is 0.5 μm × 0.5 μm which is also roughly the size of endosomes seen in this cell type [μm in size. Therefore, the targeted nanosensors encompass single pixels on average. However, it is uncertain if multiple nanosensors are present within an individual pixel. At fifteen minutes, approximately 400 pixels have SERS signal above the threshold. Over the course of an hour, the number of pixels with SERS signal swells to its peaks at approximately 1200. Over the subsequent thirty minutes, the number of pixels measured decreases to just fewer than 400. The rise in pixels over the first hour after nanoparticle delivery is explained by the slower cell processes expected to occur at 25°C compared to normal cellular growth temperature of 37°C. The nanosensors delivered suggest that the washing step did not completely remove free nanosensors. The drop in total pixels after one hour could possibly result from the degranulation process, where the nanosensors are excreted from the cells over time. In addition, it is possible that some of the nanosensors are being destroyed by the interrogation of the laser or being chemically modified by the harsh environment of the endosome. The possibility also exists that the nanosensors are aggregating, causing a decrease in pixel number without a loss of nanosensors. The total intensity of SERS signal per pixel and how this measurement corresponds to the numbers of nanosensors present was performed. The total signal intensity of the two pH sensitive 4-MPy peaks from 1500 cm−1 to 1626 cm−1 with a baseline subtraction from 900 cm−1 to 2200 cm−1 at each pixel was generated. All pixels with relevant SERS spectrum were used in the analysis. The primary Y axis is representative of the total SERS intensity counts for each image at the respective time point. The average intensity per pixel is also plotted in Y axis just as the pixel number does. The trends for SERS intensity and pixel number appear to be quite similar. The average intensity per pixel plot depicts a nearly linear 1 : 1 ratio of SERS signal to pixel number. This data lends to elimination of nanosensors from the cells rather than aggregation. Since the ratio is not exactly 1 : 1, there might be a minor contribution of nanosensor aggregation or a slight difference in nanosensor size leading to minor signal enhancements. The number of pixels having significant SERS signal is plotted in ell type . The tar−1 signal has been plotted and normalized to total pyridine signal and averaged over time. The pH dependence shows a near-linear trend that the integrated SERS signal increases with increasing acidity by approximately 23% when changed from 7.0–7.5 range to 4.5–5.0 range. The percentages of particles within pH categories which correspond to hypothetical states in the endosome maturation pathway are recorded over time [Comparison of integrated intensities of nanosensors over time and space indicated that most of the decrease in pixels seen is from elimination. Further, it would be ideal to be able to more specifically quantify the number of nanosenors within each endosome compartment so that endosome-specific information can be attributed, or that single endosome compartments can be followed over space and time. In ver time . These dεRI crosslinking leads to marked endocytosis of the receptors over a 2–12-minute time period.SERS-targeted nanosensors were added to cells held at either 37°C or 25°C. As expected, there was a considerable delay in receptor internalization in cells incubated at 25°C . AccordiExperiments performed at 25°C demonstrate the temperature dependence of both initial receptor-mediated internalization of sensors and their slower progress through the endocytic pathway. When compared to cells incubated at 37°C, it is notable that nanosensors tend to accumulate in the pre-endosomal/recycling endosomes at the lower temperature. There is also a notable retention of the total number of nanosensors within the lowest pH compartments, as expected if the low temperature slows the arrival of receptor-nanosensor complexes into secretory lysosomes and their subsequent return to the plasma membrane by exocytosis. increases in pH within endosomes of cells treated with bafilomycin, an inhibitor of the H+ ATPase pump that pumps H+ into the endosomal vesicle [+/H+ exchanger. This results in impairment of H+ exit from the endosomal vesicle and a decrease in endosomal pH [The targeted nanosensors were validated through a pharmacologic approach. First, the ability of the nanosensor to detect  vesicle –57, was somal pH –60. In bμM) and pixel size (0.5 μM × 0.5 μM), it is assumed that there is at least one nanosensor per active pixel with a possibility for multiple nanosensors to be present per pixel  within the same time of exposure . It can Bafilomycin-treated cells took up an average of 150 nanosensors during the 10 min exposure, with no obvious decline over the 40-min chase period . As showThe protocol was varied in two ways: by (1) uptake of nanosensors by untreated cells at 37°C, followed by the addition of drugs and imaging or (2) treatment with drugs and nanosensors, followed by the removal of the drugs and imaging to follow recovery of compartments. Acute effects of amiloride treatment on cells were also examined in The final set of experiments compared the uptake and transiting of nanosensors in cells pretreated with amiloride or bafilomycin but held at 25°C for all treatments. Under these conditions, untreated cells and amiloride-treated cells show a slow uptake of nanosensors, reaching similar plateau levels at approximately 45 min . In cont+/H+ exchanger on their membranes. Analysis of the pH environment for internalized receptors under each condition suggests complex effects of low temperature on receptor trafficking through the endosome-lysosome systems. A spatial view of nanosensor localization within the untreated and treated cells at 15, 40, and 60 minutes is demonstrated . In untrin vivo calibration data, can be used to create whole-cell, time-dependant localized pH maps. The targeted nanosensors show the markedly slow progression of receptors through the endocytic pathway when cells are held at 25°C. The targeted nanosensors reported the effects of H+ flux inhibiting drugs amiloride and bafilomycin on the endocytic compartments, providing reliable measurements of changes in lumenal pH. This technology represents a novel approach to use live cells as microlaboratories by developing nanosensors based on a nanoparticle platform and an abundance of ligand possibilities for sensing and targeting. The versatility of these probes shows promise for future applications relevant to intracellular trafficking and intelligent drug design.The development of targeted SERS pH nanosensors and the first applications of this technology have been demonstrated in live cells using time lapse Raman spectral microscopy. These experiments demonstrate that targeted nanosensors can be taken up by receptor-mediated internalization, providing a mechanism to simultaneously measure endocytic vesicle pH and follow the temporal and spatial progression of receptors as they traffic through the endosome-lysosome system. The ligands used for targeting and sensing have been shown to not significantly interfere with each other's function. As is demonstrated, confocal hyperspectral SERS whole-cell imagery can be rapidly acquired overtime. The imagery, with


Objective. To investigate the relationship between weight catch-up growth and insulin sensitivity in small for gestational age (SGA) infants. Methods. Forty-four singleton SGA subjects met the inclusion criteria and finished-3-month followup. Body weight, length, fasting glucose, and fasting insulin (FI) levels were measured at 3 days and 3 months. Insulin sensitivity was evaluated by FI and homeostasis model assessment (HOMA). Results. According to the change of weight Z-score, forty-four subjects were divided into two groups: noncatch-up growth (NCUG) and catch-up growth (CUG). By 3 months of age, the body weight, body length and BMI of NCUG group were significantly lower than those of CUG group. The FI and HOMA were significantly higher in NCUG group. The change of weight Z-score during 3 months was inversely related to the HOMA at 3 months. Conclusion. Our data exemplified that no weight catch-up growth during the first 3 months was associated with impaired insulin sensitivity in SGA infants. The term “small for gestational age” (SGA) is sometimes used synonymously with low birth weight, but actually it refers to a low birth weight with respect to gestational age read on references curves and not a low birth weight per se. During the past decades, dozens of epidemiological studies associated with low birth weight infants confirmed programming hypotheses first proposed by Barker et al. in 1989 , such asCatch-up growth is the acceleration in growth of 85%–90% SGA infants soon after birth . MaximumThe aim of this study was to examine the relationship between the weight catch-up growth and insulin sensitivity in SGA infants during the first 3 months of life.The subjects in our study were recruited from singleton newborns that were delivered from June through December 2009 in the department of obstetrics and subsequently followed in the department of pediatrics of the Third Hospital, Peking University.  Neonates were included in this study if they met the following inclusion criteria: (1) they had experienced a normal pregnancy with gestational age of >33 weeks; (2) their birth weights were below the 10th percentile of the sex-specific distribution for gestational age using birth weight standards of Chinese; (3) they had a 1-minute Apgar score of >7 and a 5-minute Apgar score of 10.  We excluded infants born to women with diabetes, gestational diabetes, or chronic hypertension, and infants who had intrauterine infections, congenital malformations, and major neonatal problems. We also excluded the infants who were not breastfed from birth to 3 months. A complete record with parental, pregnancy, and perinatal information was filled at entry. Clinical data were collected prospectively. These included gestation, mode of delivery, birth weight, and length and Apgar scores of 1 minute and 5 minutes.The study protocol was approved by the Ethics Committee of Third Hospital, Peking University. Subjects' parents gave informed written consent before enrollment. The investigation conformed to the principles outlined in the Declaration of Helsinki as revised in 2000.Midwives measured the birth weights and crown-heel lengths within 2 hours of delivery. Birth weights were recorded to the nearest gram using a balance scale. The crown-heel lengths were measured with a length board by the standard anthropometric technique. A single neonatal pediatrician performed gestational age assessment on each study participant according to the Dubowitz Scoring System within 48 hours of birth. Infancy weight and length were measured by standard clinical procedures during routine visits at Pediatric Department at age of 3 months (with corrected age for preterm infants).Subjects were breastfed from birth until 3 months.Blood was obtained by heel prick before feeding between 7:00 and 9:30 AM (≥2 hours' fast) on 3 days post of delivery and 3 months of age (with corrected age for preterm infants) and analyzed for fasting glucose (FG) and fasting insulin (FI) concentration. μIU/mL (1.81 pmol/L) in our laboratory, and the intra- and interassay coefficients of variation were 2.6% and 5.2%, respectively.Glucose concentrations were measured by using the SureStep Plus System from LifeScan . Interassay and intra-assay coefficients of variation for glucose were 0.9% and 1.8%, respectively. Insulin was measured by enzyme-amplified immunoassay using active insulin ELISA Kit . The detection limit of this assay was 0.26 Catch-up growth outcomes in 3 months were described using the standard deviation (SD) scores, or Z-scores, calculated from the normal population of the same chronological age and gender of Chinese. Weight Z-score were calculated according to the following equation: weight Z-score = /SD. The Z-scores of weight was calculated at birth and 3 months of age (with corrected age for preterm infants). μU/mL) × glucose (mmol/L)]/22.5]. Birth size and shape measures were birth weight, birth length, and ponderal index (PI = [birth weight (g)/birth length (cm)3] × 100)  × 100) , studiedThe weight catch-up growth was evaluated by the change between the weight Z-scores at birth and at 3 month. The change of weight Z-score during the 3 months less than  0 Z-score was defined as noncatch-up growth (NCUG) and that greater than 0 Z-score was defined as catch-up growth (CUG).t-test and Pearson χ2 test. FI and HOMA were logarithmically transformed (log 10 ) before the analysis to approach normal distribution. The relationship between the change of weight Z-score and logarithmically transformed HOMA was evaluated by Pearson correlation. P < .05 was considered statistically significant. All statistical analyses were performed using the Statistical Package for Social Science program .The data were expressed as mean ± SD. Differences between the 2 groups were compared by unpaired Student's Parents of sixty-two SGA infants gave initial consent, and blood samples were obtained in 58 at birth. Fifty-four collections met the above inclusion criteria, and forty-four subjects finished the 3-month followup, thus were taken into the scope of the study. They had no major neonatal problems and had normal acid-base status at birth. There was no history of maternal hypertension, diabetes, or infections. Mean gestational age and birth weight of the study population were 36.46 ± 2.38 weeks and 1996.59 ± 353.15 g, respectively. The male/female ratio was 22 : 22. Because there were no significant differences between the two genders, we combined the data into one group. n = 12) and catch-up growth (CUG) group (n = 32). Demographic characteristics of gender, maternal age, gestational age, delivery method, and 1-minute Apgar score were not different between two groups (All 44 SGA infants were divided into two groups according to our criteria of weight CUG: noncatch-up growth (NCUG) group   at 3 months ( = .035) .This study presents data on the development of insulin sensitivity in term and near term SGA infants from birth to 3 months. There were significant differences in weight, length, BMI, fasting insulin, and HOMA between the SGA infants with and without weight catch-up growth, and no weight gain was inversely related to HOMA by 3 months. We found that if there was no gain in weight SD score during the first 3 months of SGA infants, their insulin sensitivity, which was assessed using fasting insulin, fasting glucose, and HOMA, was relatively impaired during this period. We chose to study SGA infants because this is one human population subject to early undernutrition and consequently marked variation in early postnatal growth. SGA infants recruited to this study were born at term or near term, had normal acid-base status at birth, no history of maternal hypertension, and were breastfed during the study. The data were, therefore, not confounded by factors that were reported previously to be associated with serum insulin. The present study has certain limitations. Our relatively small sample size and short duration of followup reduced the power to robustly predict impaired insulin sensitivity related to weight catch-up growth. Furthermore, our study was restricted to SGA infants who were born in our hospital. Selection bias may have occurred to the extent that only babies born in the hospital were studied. The relationship between insulin sensitivity and catch-up growth of weight remains controversial. Singhal et al. found that later insulin resistance was greatest in infants born preterm with accelerated growth in the first 2 weeks , the perOn the contrary, Barker et al. found that raised fasting plasma insulin and proinsulin concentrations, two measures of insulin resistance , were asOur finding suggests that noncatch-up growth during the first 3 months may have adverse long-term implications for insulin resistance. One possible mechanism exists by which reduced fetal and infant growth and accelerated weight gain after 1 or 2 years may lead to insulin resistance. SGA infants who are thin at birth lack muscle, a deficiency which will persist, as there is little cell replication after birth . They coIn conclusion, the present study demonstrates that SGA infants without weight catch-up growth during the first 3 months of life present relatively impaired insulin sensitivity. Although the role of early postnatal growth from birth to two years of age remains unresolved, our current study provides much more precise information on the timing of the weight gain that appears to be related to later health. Because of the limitation of the study, we believe that a larger sample size with more AGA infants as a control group addressing the impact of catch-up growth on insulin sensitivity could provide a more robust result.


Many stillbirths show evidence of fetal growth restriction, and most occur at preterm gestational age. The objective of this study is to compare birth weights at preterm gestational ages between live births and stillbirths, and between those occurring before or during labour.Based on singleton births from the United States (U.S.) 2003–2005  and Sweden 1992–2001 , we compared birth weights between singleton live births and stillbirths at 24–36 completed weeks of gestation from the U.S. and at 28–42 completed weeks from Sweden.In both the U.S. and Sweden, stillbirth weight-for-gestational-age z-scores were at least one standard deviation lower than live birth z-scores at all preterm gestational ages (GA). In Sweden, no birth weight difference was observed between antepartum and intrapartum stillbirths at preterm GAs, whereas birth weights among intrapartum stillbirths were similar to those among live births at 37–42 weeks.Birth weights observed at preterm gestation are abnormal, but preterm stillbirths appear to be more growth-restricted than preterm live birth. Similar birth weights among ante- and intrapartum preterm stillbirths suggest serious fetal compromise before the onset of labor. Depending on jurisdiction, stillbirth is variably defined as a fetal death from 20, 22, 24 or 28 completed weeks of gestation and can also depend on birth weight -4. In thThe actual time of fetal death is usually unknown. It has been reported that stillbirths are generally delivered within 24 hours of diagnosis -14, and We used period linked birth-infant death data and fetal death data files from the National Vital Statistics System of the United States for the years 2003, 2004, and 2005. These publicly available data files, compiled by the U.S. National Center for Health Statistics (NCHS), include information from the birth certificate on maternal socio-demographic characteristics, birth weight, period of gestation, plurality, and live birth order and is linked to information from the infant death certificate. The fetal death files include information from all reports of fetal deaths but do not include the cause of stillbirth . In the In the United States, gestational age (GA) is usually calculated from the first day of the mother’s last menstrual period (LMP). It has been shown that gestational age derived from the LMP estimate is prone to error, especially for postterm dates -25. The We restricted our primary analysis to singleton births 24–36 completed weeks of gestation. We also excluded implausibly high or low birth weights at given gestational ages from our study sample, based on Table To guard against potential misclassification of GA in the US birth cohort ,25, we a2, which predicts a mean birth weight of 3619 g at 280 days. Hadlock’s formula assumes proportional fetal growth throughout pregnancy and models fetal growth trajectory “by dividing each daily value predicted by this formula by the 280-day value and fitting a third-degree polynomial of gestational age”, which yields the following “proportionality equation” for GAs of 24–39 weeks [2 – 0.01055 × GA3.To evaluate fetal growth, we used estimated fetal weight as the reference standard, rather than the observed birth weight, since the latter is known to be suboptimal at preterm GAs ,22. Inte39 weeks : % EFW =The latter equation can then be used for any estimated 280-day birth weight to estimate fetal weight in 24–39 weeks of gestational age. Sex-specific birth weight z-scores for 40 weeks of gestation were first calculated based on the study sample, and the sex-specific weight-for-gestational-age z-scores were then extrapolated backward by the proportionality equation. Further details have been described in previous studies ,30,31. HThe primary outcomes were birth weight and birth weight-for-gestational-age z-score. We compared mean birth weights and birth weight-for-gestational-age z-scores at preterm gestations between singleton stillbirths and live births at 24–36 weeks of gestation from the U.S. and at 28–36 weeks from Sweden. We further compared birth weight-for-gestational-age z-scores between antepartum and intrapartum Swedish stillbirths both at preterm and term gestations. For all these comparisons, we used two-sample t-test. At each completed week of gestation, stillbirth weight was also expressed as a percentage of the mean (POM) of live birth weights at the same gestation; the mean of these percentages, with its 95% confidence interval (CI), was then calculated. We also carried out race/ethnicity-specific analyses of non-Hispanic Whites, non-Hispanic Blacks, and Hispanics, from the U.S. and compared birth weights among antepartum and intrapartum stillbirths from Sweden. Finally, as a sensitivity analysis, we excluded from the U.S. birth cohort all births diagnosed with congenital anomalies at birth and compared birth weight between preterm live births and stillbirths. All analyses were carried out using SAS version 9.2 .Figure We observed similar patterns in birth weight and z-score differences between live births and stillbirths in race/ethnicity-specific analyses of U.S. non-Hispanic Whites, non-Hispanic Blacks, and Hispanics (data not shown) as we did in the overall U.S. study sample. After excluding all births diagnosed with congenital anomalies at birth, we observed a similar patterns of birth weight and z-score differences between preterm live births and stillbirths (data not shown), although the average difference in birth weight decreased from 1,013 to 876 g.Table Average birth weights are known to be lower than intrauterine  weights early in pregnancy ,22, stroAs shown in our study, stillbirth weights were at least one SD below live birth weights at preterm GAs. The fact that stillbirths weigh less at delivery than live births at the same GA has been previously documented ,35. PrevIn our analysis of the Swedish data, we were surprised not to observe significant birth weight differences between antepartum and intrapartum stillbirths at preterm GAs. This result does not agree with previous reports by Chard  and AlbeAssuming little or no weight loss among most antepartum stillbirths from death to delivery, preterm stillbirths appear to be more growth-restricted than live births at the same GA. It has been shown that size at birth is affected by growth velocity early in gestation and that growth restriction diagnosed at delivery is preceded by slower first- and early second-trimester fetal growth ,38. As sAn important limitation of our study is the lack of a good ultrasound-based fetal weight reference at preterm gestations, which would improve estimation of the difference between the birth weights of live births and the fetal weights of their counterparts who remain in utero. Hadlock’s fetal growth curve , based oOur study is further limited by the use of nation-wide vital statistics databases, in which coding errors are known to occur ,40. In pMany preterm births are growth-restricted. Our study suggests that growth restriction is a cumulative process and that those fetuses who subsequently die preterm in utero grow even more slowly then those born alive at the same GA. Reduced placental blood supply and the consequent reduction in delivery of oxygen and nutrients to developing fetuses may both restrict fetal growth early in gestation and increase the risk of subsequent stillbirth. Suboptimal placental function and poor growth early in pregnancy limit fetal growth for the remainder of pregnancy. Early and routine ultrasound scans to monitor fetal size and growth during pregnancy might theoretically reduce the risk of stillbirth. This is perhaps the most important clinical implication of our findings. Before implementing routine clinical monitoring, however, an improved intrauterine fetal weight reference is required. Large-scale NIH-  and Gates Foundation-funded studies of ultrasound-based fetal size assessment currently under way should provide much-needed data on normal fetal growth patterns. Future research should attempt to understand the pathophysiological mechanisms underlying growth restriction, as a basis for developing and testing preventive and therapeutic interventions to reduce stillbirth risk.Birth weights observed at preterm gestation are abnormal, but preterm stillbirths appear to be more growth-restricted than preterm live birth. Similar birth weights among ante- and intrapartum preterm stillbirths suggest serious fetal compromise before the onset of labor.We have declared no conflict of interest.Dr. XZ designed the study, performed the statistical analyses, and wrote the first draft of the manuscript. Drs. KSJ, SC, and MSK all contributed to the study design, interpretation of results, and manuscript revisions. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/12/119/prepub