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Liver disease associated with occupational exposure to the solvent dimethylformamide.
ABSTRACT to characterize an outbreak of liver disease among workers in a fabric coating factory; and to determine the outbreak's cause and natural history and strategies for clinical recognition, treatment, and prevention.
clinical-epidemiological investigation.
academic medical center, Occupational Medicine Clinic, and worksite.
fifty-eight of sixty-six workers participated in the study. All had standard liver function tests at least once. Forty-six workers completed a questionnaire; 27 had more extensive clinical evaluation for recognized liver abnormalities.
a plant-wide outbreak of liver disease was recognized after a new employee presented with signs and symptoms of hepatitis. Evaluation of the worksite showed that dimethylformamide, a widely used industrial solvent and known hepatotoxin, was being used to coat fabric in poorly ventilated areas without appropriate skin protection. No other major hepatotoxic exposure was identified. Overall, 36 of 58 (62%) workers tested had elevations of either aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels. Enzyme abnormalities occurred almost exclusively in production workers (35 of 46 were abnormal), whereas only 1 of 12 nonproduction workers showed any elevations in enzyme levels (P less than 0.0001). Serologic tests excluded known infectious causes of hepatitis in all but 2 workers and changes characteristic of toxic liver injury were confirmed by histologic examinations of biopsy specimens from 4 workers. The ratio of AST to ALT levels was one or less in all but 1 worker. After modification of work practices and removal of workers most severely affected from exposure, improvement in liver enzyme abnormalities and symptoms in most patients were seen, although some patients showed persistent elevations of enzyme levels.
an outbreak of toxic liver disease has been associated with exposure to dimethylformamide in the workplace. The diagnosis of toxic liver disease was established by the clinical histories, negative viral serologies, an enzyme pattern of ALT levels being greater than AST levels, epidemiologic data on coworkers, and liver biopsy specimens. The high prevalence of unsuspected liver enzyme abnormalities in these workers suggests that occupational liver disease may occur more frequently than is generally recognized.
- [Show abstract] [Hide abstract]
ABSTRACT: A diffusive sampling method with water as absorbent was examined in comparison with 3 conventional methods of diffusive sampling with carbon cloth as absorbent, pumping through National Institute of Occupational Safety and Health (NIOSH) charcoal tubes, and pumping through NIOSH silica gel tubes to measure time-weighted average concentration of dimethylformamide (DMF). DMF vapors of constant concentrations at 3–110 ppm were generated by bubbling air at constant velocities through liquid DMF followed by dilution with fresh air. Both types of diffusive samplers could either absorb or adsorb DMF in proportion to time (0.25–8 h) and concentration (3–58 ppm), except that the DMF adsorbed was below the measurable amount when carbon cloth samplers were exposed at 3 ppm for less than 1 h. When both diffusive samplers were loaded with DMF and kept in fresh air, the DMF in water samplers stayed unchanged for at least for 12 h. The DMF in carbon cloth samplers showed a decay with a half-time of 14.3 h. When the carbon cloth was taken out immediately after termination of DMF exposure, wrapped in aluminum foil, and kept refrigerated, however, there was no measurable decrease in DMF for at least 3 weeks. When the air was drawn at 0.2 l/min, a breakthrough of the silica gel tube took place at about 4 000 ppm min (as the lower 95% confidence limit), whereas charcoal tubes could tolerate even heavier exposures, suggesting that both tubes are fit to measure the 8-h time-weighted average of DMF at 10 ppm.International Archives of Occupational and Environmental Health 12/1991; 63(7):449-453. · 2.10 Impact Factor
Article: Inactivation of rat liver cytochrome P450 (P450) by N,N-dimethylformamide and N,N-dimethylacetamide.[Show abstract] [Hide abstract]
ABSTRACT: N,N-dimethylformamide (DMF), an organic solvent widely used in industry, is bioactivated by cytochrome P450 (P450) to reactive metabolites which are believed to be responsible for the hepatotoxicity observed in animals and humans. A decrease of the activating enzyme has been reported in rats treated with DMF, although the specific P450 isoform(s) involved and the nature of the reactive species responsible for this and the other toxic effects are still being investigated. In the present work, the effect of DMF and of the structurally related N,N-dimethylacetamide (DMAc) on the activating enzyme and the nature of the reactive species involved in the mechanism of P450 inactivation by the two chemicals were investigated in vitro. Incubation of liver microsomes from pyridine-induced rats with either substrate resulted in a dose-dependent (0-20 mM) loss of P450 (up to 28 and 24% for DMF and DMAc, respectively), microsomal haem (up to 24 and 20% for DMF and DMAc, respectively), but not protoporphyrin IX content. Moreover, bubbling of CO through the incubation mixture gave almost complete protection against substrate-dependent P450 inactivation, and the spin trapping agent N-tert-butyl-alpha-phenylnitrone, but neither glutathione nor vitamin C, provided a significant protection against DMF- or DMAc-dependent haem loss. Finally, electron spin resonance analysis of microsomal incubations in presence of DMF or DMAc showed spectral evidence for a carbon centered radical intermediate. The results indicate, overall, that both compounds are metabolized in vitro by P450, probably CYP2E1, to free radical metabolites which attack the haem prosthetic group, leading to suicidal enzyme inactivation.Toxicology Letters 11/2001; 124(1-3):101-11. · 3.15 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: A factory survey was conducted in a plant whereN,N-dimethylformamide (DMF) was in use during the production of polyurethan plastics and related materials. In all, 318 DMF-exposed workers (195 men and 123 women) and 143 non-exposed controls (67 men and 76 women) were examined for time-weighted average exposure (to DMF and other solvents by diffusive sampling), hematology, serum biochemistry, subjective symptoms, and clinical signs. Most of the exposed workers were exposed only to DMF, whereas others were exposed to a combination of DMF and toluene. DMF exposure in the former group was up to 7.0 ppm (geometric mean on a workshop basis), whereas it was up to 2.1 ppm in combination with 4.2 ppm toluene. Both hematology and serum biochemistry, results (including aspartate and alanine aminotransferases, -glutamyl transpeptidase and amylase) were essentially comparable among the 3 groups. There was, however, a dose-dependent increase in subjective symptoms, especially during work, and in digestive system-related symptoms such as nausea and abdominal pain in the past 3-month period. The prevalence rate of alcohol intolerance complaints among male (assumedly) social drinkers was also elevated in relation to DMF dose.International Archives of Occupational and Environmental Health 12/1991; 63(7):461-468. · 2.10 Impact Factor
Page 1
Liver Disease Associated with Occupational Exposure to the Solvent
STUART L SHALAT, Sc.D.; and MARK R. CULLEN, M.D.; New Haven, Connecticut
Study Objective: To characterize an outbreak of liver dis-
ease among workers in a fabric coating factory; and to deter-
mine the outbreak's cause and natural history and strategies
for clinical recognition, treatment, and prevention.
Design: Clinical-epidemiological
Setting: Academic medical center, Occupational Medicine
Clinic, and worksite.
Patients: Fifty-eight of sixty-six workers participated in the
study. All had standard liver function tests at least once. For-
ty-six workers completed a questionnaire; 27 had more ex-
tensive clinical evaluation for recognized liver abnormalities.
Results: A plant-wide outbreak of liver disease was recog-
nized after a new employee presented with signs and symp-
toms of hepatitis. Evaluation of the worksite showed that di-
methylformamide, a widely used industrial solvent and known
hepatotoxin, was being used to coat fabric in poorly ventilat-
ed areas without appropriate skin protection. No other major
hepatotoxic exposure was identified. Overall, 36 of 58
(62%) workers tested had elevations of either aspartate ami-
notransferase (AST) or alanine aminotransferase (ALT) lev-
els. Enzyme abnormalities occurred almost exclusively in pro-
duction workers (35 of 46 were abnormal), whereas only 1 of
12 nonproduction workers showed any elevations in enzyme
levels (P < 0.0001). Serologic tests excluded known infec-
tious causes of hepatitis in all but 2 workers and changes
characteristic of toxic liver injury were confirmed by histolog-
ic examinations of biopsy specimens from 4 workers. The
ratio of AST to ALT levels was one or less in all but 1 worker.
After modification of work practices and removal of workers
most severely affected from exposure, improvement in liver
enzyme abnormalities and symptoms in most patients were
seen, although some patients showed persistent elevations
of enzyme levels.
Conclusions: An outbreak of toxic liver disease has been
associated with exposure to dimethylformamide in the work-
place. The diagnosis of toxic liver disease was established by
the clinical histories, negative viral serologies, an enzyme
pattern of ALT levels being greater than AST levels, epidemi-
ologic data on coworkers, and liver biopsy specimens. The
high prevalence of unsuspected liver enzyme abnormalities
in these workers suggests that occupational liver disease
may occur more frequently than is generally recognized.
LIVER DISEASE due to occupational exposure is believed
to be an uncommon event in modern industry (1). Liver
disease from exposure to well-recognized industrial hepa-
totoxins such as carbon tetrachloride,
pesticides including chlordecone (kepone), and yellow
phosphorus is also rarely seen. The incidence and natural
history of occupationally induced toxic liver injury are
not well defined, nor are strategies for differentiating it
from other causes of hepatitis. These issues were studied
during a recently recognized outbreak of liver disease in
New Haven, Connecticut, associated with occupational
exposure to the widely used industrial solvent dimethyl-
Because of its excellent solvent properties, dimethylfor-
mamide is a versatile and widely used industrial
chemical. It is used primarily in the manufacture of
polyurethane products and acrylic fibers, as well as the
production of pharmaceuticals, pesticides, and in other
various applications. Dimethylformamide use is pre-
sumed to be widespread based on the estimated 33 mil-
lion pounds produced in the United States in 1979, but
there is no reliable estimate of the number of workers
currently exposed (2). Animal studies have shown that
dimethylformamide is hepatotoxic in several species in-
cluding cats, mice, rats, guinea pigs, and rabbits (3-10).
Dimethylformamide is readily absorbed through the skin,
respiratory system, and gastrointestinal tract. The pri-
mary organ of toxicity is the liver, which on histologic
examination shows evidence of hepatic necrosis.
However, the effects of dimethylformamide exposure
in humans are not as well documented. Complaints of
abdominal pain, nausea, vomiting, dizziness, headaches,
loss of appetite, and alcohol intolerance have been report-
ed in workers exposed to dimethylformamide (11-17).
Although liver function has rarely been evaluated in such
workers, abnormal liver function tests have been seen in a
few instances (13, 14), primarily after large accidental
exposures. Several studies (3, 18) have found no evidence
of hepatotoxicity after more routine exposures to dimeth-
After the referral of a worker with suspected toxic hep-
atitis, we did a clinical-epidemiologic investigation of his
coworkers and an environmental assessment of the work-
Case Report
A previously healthy 40-year-old Hispanic man presented to
the emergency room at Yale-New Haven Hospital with abdomi-
nal pain, nausea, and headache in October 1986. He had be-
come ill after working for less than 2 weeks as an operator of a
fabric-coating machine. He reported that other workers had
©1988 American College of Physicians
• From the Occupational Medicine Program and Liver Study Unit, Department
of Internal Medicine, and Department of Pathology, Yale University School of
Medicine; New Haven, Connecticut.
6 8 0 Annals of Internal Medicine. 1988;108:680-686.
Page 2
Figure 1A. Liver biopsy specimens
of an index case (Patient 1). A cen-
trilobular and midzonal
shows lobular disarray and regen-
erative changes of irregular liver
cell plates, binucleated
cytes, and variation in nuclear size
and configuration. Enlarged Kupff-
er cells are present {arrows),
inconspicuous. (Hematoxylin and
eosin; original
100.) Figure IB.
material in Kupffer cells stains pos-
itively, enabling them to be seen
easily. (Periodic acid-Schiff; Origi-
nal magnification x 100.)
magnification x
similar symptoms. Standard liver function tests showed an ele-
vated aspartate aminotransferase (AST) level of 15.8 u.kat/L
(normal, 0.25 to 0.58 u.kat/L). Alkaline phosphatase and bili-
rubin levels were normal. Hepatitis A IgM antibody and hepati-
tis B surface antigen and antibody were negative, as was an
abdominal ultrasound. The patient had no history of significant
alcohol use, blood transfusions, or intravenous drug use. Based
on a presumptive diagnosis of toxic hepatitis, he was removed
from his workplace. His symptoms resolved and his transami-
nase levels improved.
A liver biopsy was done 3.5 months later because of persist-
ently elevated liver enzymes (alanine aminotransferase [ALT]
levels, three times control). Microscopic examination showed
changes consistent with a resolving toxic injury to the liver,
including evidence of diffuse regeneration with irregular liver
cell plates, binucleated hepatocytes, and variation in nuclear
size and staining characteristics (Figure 1A). In addition there
was spotty unicellular necrosis and, on staining with periodic
acid-Schiff-diastase, enlarged Kupffer cells were seen in the si-
nusoids (Figure IB). A fat stain on a cryostat section of the
biopsy specimen showed diffuse steatosis in a microvesicular
pattern, which was not evident on conventionally prepared par-
affin sections. There was no evidence of chronic disease. Six
months after removal from work, transaminase levels had re-
turned to normal.
The company produces polyurethane-coated fabrics. Large
amounts of dimethylformamide and lesser quantities of other
solvents including toluene, methylethylketone, 1,1,1 trichloro-
ethane, and dichlorobenzene are mixed with polyurethane com-
ponents, including diisocyanates, in a mixer. The polyurethane-
solvent mixture is then poured into smaller containers and hand
ladled onto moving fabric. Dimethylformamide and other sol-
vents evaporate from the fabric as it dries. The finished product,
rolls of polyurethane-coated fabric, is used to make bullet-proof
vests, parachutes, and other items.
Industrial hygiene evaluation of the workplace was limited to
general observation because the company curtailed production
shortly after the results of the screening liver function tests were
obtained and before measurements of air concentrations of in-
dustrial solvents could be taken.
The workforce consists of nonproduction workers such as
office staff, management, inspectors, and supervisors; and pro-
ductions workers such as machine operators, helpers, and mix-
ers. Nonproduction employees work primarily in the office and
inspection areas. Most of the production employees work on
one of six coating machines. A few persons work in a separate
shed mixing solvents and polyurethane components. Historical-
ly, job turnover has been rapid with frequent switching of job
categories. Precise information on the total number of employ-
ees newly hired or terminated was not available.
The company supplied a list of all sixty-six current employ-
ees, but information such as job category or length of employ-
ment was not made available. The employer had not obtained
any medical information about his workers. As a result of the
clinical findings in Patient 1, arrangements were made to do
screening liver function tests on all employees. The initial
screening liver function tests on 45 employees included AST,
ALT, gamma-glutamyl transpeptidase, direct and total biliru-
bin, alkaline phosphatase, lactic dehydrogenase, total protein,
and albumin levels. An additional 11 employees had liver func-
tion test drawn over the next 3 months, either because they
missed the initial screening or joined the workforce after that
Individual liver function test results and a questionnaire to
determine demographic background, job history, and symptoms
were sent to all workers. Those workers with ALT or AST
levels greater than twice normal were referred to the Occupa-
tional Medicine Clinic; any other worker who wished to be
evaluated was also seen. Thus, 27 workers were evaluated in the
Occupational Medicine Clinic.
Evaluation consisted of a history, physical examination, labo-
ratory work including liver function tests, hepatitis A and B
serologies, complete blood count, prothrombin time, and partial
thromboplastin time. Additional blood tests including determi-
nation of blood urea nitrogen, creatinine, glucose, and electro-
lyte levels were done on many. Four had liver biopsies done;
five had abdominal ultrasound examinations. For analysis of
liver function test data, the highest enzyme elevations were used
for all patients with two or more complete sets, unless otherwise
Large quantities of dimethylformamide (approximate-
ly 15 to 20 fifty-five gallon drums per week) and lesser
amounts of other solvents including toluene (10 drums
per week), methylethylketone (5 to 10 drums per week),
1,1,1 trichloroethane (5 drums per week), and dichloro-
benzene (0.5 drums per week) were being used in poorly
ventilated areas without appropriate skin protection. The
Redlich etal. • Exposure to Dimethylformamide 6 8 1
Page 3
Figure 2. The workplace where em-
ployees were exposed to dimethyl-
iformamide. One of the fabric-coat-
ing machines after local ventilation
had been installed, and a nearby
barrel containing a mixture of di-
and other solvents are shown {left).
The previous inadequate ventila-
tion system is also shown {right).
work areas where the coating machines and mixer were
located had little ventilation (Figure 2). The workers op-
erating the machines did not routinely wear protective
clothing and had considerable gross skin contamination
by the solvents. The drums and smaller cans containing
the solvents and polyurethane mixture frequently were
unlabeled and left uncovered.
Including the index case, data were available on 58 of
66 employees (Figure 3). Forty-six of these 58 either
returned the questionnaire or were interviewed in the
clinic. Average length of employment was 40 months, but
15 had worked for 3 months or less. Eighty-one percent
of the employees were Hispanic, 14% were white. The
mean age of the 58 workers tested was 33 years (range,
18 to 60). All but 2 workers were male.
A worker was classified as a production worker if he
had worked at one of the production jobs within the past
6 months. The job classification of the 12 workers who
did not fill out questionnaires was based on the question-
ing of other workers and management. By these criteria,
46 employees were considered production workers, and
12 were nonproduction workers (Figure 3). All produc-
tion workers were men who worked 12-hour shifts 5 days
per week. Many also worked additional 8-hour shifts on
weekends. All but 3 production workers were Hispanic;
many did not speak English. One third of the nonproduc-
tion workers were Hispanic; two were female. Most of
the 8 workers who did not participate appeared to be
nonproduction personnel.
Overall, 36 (62%) workers had elevated AST or ALT
levels. Nineteen (33%) had elevations greater than twice
normal (Figure 3). Nine of these nineteen had enzyme
elevations greater than five times normal. At least 4 had
sought medical attention for symptoms similar to Patient
Liver enzyme levels correlated with job classification
(Figure 3). Of the 12 nonproduction workers, 11 had
normal transaminase levels; only 1 had mild elevations.
Of the 46 production workers, 35 had some elevation in
liver enzyme levels and 19 had elevations greater than
twice normal of one or more liver enzyme. Only 11 had
normal liver enzyme levels. The mean ALT level for non-
production workers was 0.50 it 0.12 u,kat/L; the mean
ALT level for production workers was 1.88 +
u,kat/L. The association between job classification and
liver function test abnormalities was highly significant us-
ing the Fisher exact test on proportions (P < 0.0001)
and the Student Mest on mean ALT levels (P < 0.01).
The ratio of AST to ALT levels was one or less in all
but one worker (Figure 4). In most workers it was less
than 0.6. This ratio is opposite of the ratio usually found
in alcoholic liver disease, in which a value of two or more
is typical (19).
Interestingly, the relation between duration of expo-
sure and transaminase levels was inverse, with short-term
workers (less than 2 months) showing the greatest ab-
normalities (Figure 5). Given the highly transient nature
of the workforce and the cross-sectional study design,
this peculiarity could not be studied further.
On the basis of the questionnaire or clinic interview
obtained from 46 workers, the following symptoms were
reported: gastrointestinal (anorexia, abdominal pain, or
nausea) in 31; central nervous system solvent intoxica-
tion (headaches, dizziness) in 18; and alcohol intolerance
characterized by a disulfiram type reaction (facial flush-
Figure 3. Flow chart showing data obtained from workers exposed
to dimethylformamide. Liver function tests were obtained from 58
of 66 employees. Forty-six of these 58 were production workers;
12 were nonproduction workers. Of the 46 production workers, 11
had normal liver enzymes; 35 had one or more elevated transami-
nase level. Of the 12 nonproduction workers, 11 had normal liver
enzymes and only one had mild elevations in transaminase levels.
LFTS = liver function tests.
6 8 2 May 1988 • Annals of Internal Medicine • Volume 108 • Numbers
Page 4
ing and palpitations after alcohol intake) in 11.
Based on these findings, cessation of production was
recommended pending the installation of appropriate
protective engineering controls. Approximately 2 months
after the initial liver screening tests were drawn, workers
went on strike.
After the initial screening, 27 workers, including all 19
with liver enzyme levels greater than twice normal,
sought medical follow-up in our clinic. Twenty-six were
production workers; one was a nonproduction worker
(Figure 3). The symptoms noted above were frequently
reported after the onset of employment at the plant. Viral
hepatitis serologies showed that all 27 had negative hepa-
titis B surface antigen and negative hepatitis A IgM anti-
body. Hepatitis B surface antibody and core antibody
were positive in 2. Only 2 workers gave a history of sig-
nificant alcohol or intravenous drug use. None had re-
ceived blood transfusions, and any use of medications
was rare. Five patients with the most significant abnor-
malities are described in the appendix.
All patients with greater than twofold elevations in
their transaminase levels were transferred to a nonpro-
duction area or removed entirely from work, depending
on their symptoms and the availability of a nonproduc-
tion job. The symptoms of all these workers improved
with removal from direct exposure to dimethylformam-
ide. In most cases transaminase levels returned to normal
or near normal in 1 to 5 months after the worker's re-
moval from the workplace. However, transaminase levels
of eight workers, all of whom have been on strike and
removed from the production area, have remained mildly
elevated or have risen slightly. Although the cause of
these persistent transaminase abnormalities is unclear, it
is possible that some of these workers have had continued
exposure to dimethylformamide through contaminated
shoes or clothing. Clinical histories have not indicated
significantly increased use of alcohol among these work-
Figure 4. Frequency distribution of the ratio of aspartate amino-
transferase (AST) to alanine aminotransferase (ALT) levels in 36
production workers exposed to dimethylformamide with one or
more elevated transaminase levels. If the patient had more than
one set of liver enzyme tests, the set with the highest AST and ALT
value was used. The ratio of AST to ALT levels was one or less in all
but 1 patient, the opposite of the ratio normally seen in alcoholic
liver disease.
Figure 5. Relationship between months of employment and alanine
aminotransferase (ALT) levels in production workers exposed to
dimethylformamide who completed a questionnaire (n = 38).
Months of employment were determined on the basis of question-
naire data and calculated from month of initial hire to the date liver
function tests were drawn. The ALT level used was from the initial
screening or from the first clinic visit if the patient had continued
exposure after the screening test.
ers or exposure to any other hepatotoxic agents during
this period.
We have characterized an outbreak of liver disease
among workers occupationally exposed to the solvent di-
methylformamide. This study addresses several impor-
tant issues about the prevalence, diagnosis, and prognosis
of toxic liver disease in the occupational setting.
Several factors may limit our ability to interpret the
observed association as causal. Despite our inability to
obtain liver function tests and questionnaires on all 66
employees, we did obtain liver function tests on 58 of 66
employees (88%), and questionnaires on 46 of these 58
(80%). Given the circumstances, including a largely
transient non-English-speaking workforce and limitations
imposed by the employer, we feel that we have sufficient
information to characterize this population.
The prevalence of abnormalities in transaminase levels
in the general population is unknown. It is possible, but
unlikely, that the elevated transaminase levels in these
workers could be due to another cause such as alcohol,
drugs, or viral hepatitis. Excessive alcohol use is probably
the most common cause of elevated liver enzymes in a
population such as this. However, we do not feel that
alcohol can explain the current findings. Detailed histo-
ries of 27 workers showed little if any excessive alcohol
consumption in most. This information was supported by
the laboratory data. The ratio of AST to ALT was almost
always less than one, a reversal of the ratio usually found
Redlich etal. • Exposure to Dimethylformamide 6 8 3
Page 5
in alcoholic hepatitis (18). In addition, none of the four
liver biopsy specimens showed changes typical of alcohol-
ic liver disease. However, alcohol use may potentiate the
hepatotoxicity of dimethylformamide. Such an interac-
tion has been shown in animals when carbon tetrachlo-
ride and ethanol or other aliphatic alcohols are combined
In most patients no other cause for the transaminase
elevations could be ascertained after evaluation in the
clinic, including a detailed history and physical examina-
tion, hepatitis A and B serologies, and liver biopsies in
three workers. Although outbreaks of non-A, non-B hep-
atitis have been described (22) and would escape serolog-
ic detection by available techniques, this interpretation
seems highly inconsistent with our epidemiologic data,
clinical findings, and liver biopsy results.
The possibility that these workers were exposed to a
liver toxin other than dimethylformamide must also be
considered. In addition to dimethylformamide these
workers used several other solvents including methyle-
thylketone, toluene, and 1,1,1 trichloroethane, and di-
chlorobenzene. These solvents have individually been
shown to have little if any hepatotoxicity in animal and
human studies; additionally, they were used in much
smaller amounts than dimethylformamide. As with alco-
hol, it is possible that some of these solvents may have
potentiated the hepatotoxicity of dimethylformamide. No
toxicologic data are available on the interaction of dime-
thylformamide with alcohol or other solvents.
In establishing a causal link, it would have been desir-
able to obtain either air samples or some biologic marker
quantifying the amount of dimethylformamide exposure.
However, we were unable to take air samples before im-
provements in the ventilation system were made, and no
good biologic marker of dimethylformamide exposure ex-
ists. It is probable that skin absorption of dimethylfor-
mamide is a more important route of exposure than inha-
lation, as most likely was the case with these workers.
Unfortunately, no accurate means of quantifying skin ex-
posure exists. Although a urine test that measures mono-
methylformamide, one of the urinary metabolites of
dimethylformamide, does exist (23-28), there is no well
established correlation between exposure to dimethylfor-
mamide and the amount of monomethylformamide in a
spot urine sample. Also, the test is not widely available,
and it was not feasible to obtain timed urine collections
from these workers before their removal from the work-
Because dimethylformamide hepatotoxicity is believed
to be dose-dependent, a direct relation between length of
exposure and elevated liver enzyme levels might be ex-
pected. Actually, the reverse was seen. One possible ex-
planation for this paradoxical finding is that workers who
became ill left the plant. The plant had a high turnover of
employees, many of whom, like several of our patients,
may have left after a few weeks because of symptoms
described above. As noted, data on hiring and termina-
tion were insufficient to adequately test this hypothesized
"healthy worker effect." Another possibility is that expo-
sure to dimethylformamide induces the enzymes that me-
tabolize it, so that workers chronically exposed develop
tolerance to its toxic effects.
Several similarities and differences between the liver
toxicity reported here and that found with carbon tetra-
chloride, the best-studied occupational hepatotoxin,
should be noted. Hepatic necrosis and steatosis, which
are typically seen with carbon tetrachloride poisoning,
were also seen in three of four liver biopsy specimens,
although findings were mild in two. These two biopsy
specimens showed evidence of resolution and regenera-
tion, however, and it is likely that the degree of hepato-
cellular injury would have been more pronounced had
biopsies been done earlier in the patients' illnesses. The
biopsy done on the worker with much longer exposure to
dimethylformamide (Patient 6) showed evidence of
moderately severe steatosis with spotty necrosis despite
only mildly elevated transaminase levels. Resolution of
the abnormalities of liver enzyme levels has taken longer
(1 to 7 or more months) in these patients compared to
that reported with carbon tetrachloride (less than 2
weeks) (1).
There are several possible explanations for this finding.
Most human data on the natural history of carbon tetra-
chloride-induced liver injury is based on single or very
short-term acute exposures, rather than weeks to years of
exposure as reported here. Some of the workers may have
had ongoing exposure to dimethylformamide after re-
moval from work through contaminated clothing and
shoes that they continued to wear. Alternately, dimethyl-
formamide may have a different mechanism of hepato-
toxicity and natural history than that of carbon tetrachlo-
Finally, several aspects of this investigation should be
emphasized for practitioners. An outbreak of liver disease
among 62% of workers in a plant has been identified,
although most workers had never sought medical atten-
tion. On the basis of an evaluation of the workplace and
workers, an industrial solvent, dimethylformamide, was
found to be the most likely cause of the problem. Both
the clinical epidemiologic data presented here and previ-
ous evidence of dimethylformamide liver toxicity from
animal and human studies were crucial factors in linking
this outbreak to dimethylformamide.
In addition, two clinical findings described in this
study could help physicians recognize potential occupa-
tional liver disease and overexposure to widely used and
potentially hazardous industrial solvents. First, the con-
sistent finding of the ratio of AST to ALT levels less than
one proved helpful in differentiating toxic from alcoholic
hepatitis, and should alert the clinician to consider such a
possibility. Accordingly, ALT measurements should be
included in liver function tests where toxic injury is being
considered. Second, the presence of acquired alcohol in-
tolerance (degreaser's flush or disulfiram symptoms)
should make clinicians consider solvent overexposure.
Such symptoms are unusual, and because they are rarely
volunteered by the patient, they should be inquired about
Several aspects of this study suggest that toxic liver
disease due to dimethylformamide or other agents may
6 8 4 May 1988 • Annals of Internal Medicine • Volume 108 • Number 5
Page 6
be more common than previously recognized. Elevated
liver enzyme levels were found in 76% of production
workers exposed routinely to dimethylformamide, with-
out accidental overexposure or unusual circumstances.
Such a high incidence of elevated liver enzyme levels was
not anticipated. Although some of these patients were
symptomatic, most had minimal symptoms and had nev-
er sought medical evaluation. In addition, during the 15
years since the factory opened, many workers may have
developed toxic hepatitis, but were never correctly diag-
nosed. Even though this factory is located within a few
miles of a community health clinic and a major academic
medical center, the problem remained unidentified until
Review of the Occupational Medicine Clinic patient
records indicated that a worker from this same plant had
been evaluated 3 years ago. Although excess solvent ex-
posure was suspected, and the patient had gastrointesti-
nal symptoms and a mildly elevated AST level (ALT
levels were not tested), the diagnosis of toxic hepatitis
had been missed. This missed diagnosis raises the con-
cern that liver injury due to dimethylformamide and pos-
sibly other industrial solvents or chemicals may frequent-
ly go undetected.
The long-term effects of dimethylformamide exposure
are not known. Although no evidence of chronic liver
disease was found in liver biopsy specimens from four
patients, three of these patients had relatively short expo-
sures (several weeks to months). This cohort of workers
will be followed to help ascertain the natural history and
long-term effects of dimethylformamide hepatotoxicity.
The mechanism whereby dimethylformamide exerts its
toxic effects, the possible interactions with other solvents
and alcohol, and the variability in individual susceptibili-
ty require further investigation.
A 20-year-old previously healthy Hispanic man had worked
at the same plant as Patient 1 for 2 weeks, applying dimethyl-
formamide onto the fabric with a ladle. He complained of
symptoms similar to symptoms of Patient 1, which developed
within the first week of his new job. His AST level was 6.92
fikat/L and his ALT level was 15.57 u,kat/L (normal, less
than 0.53 jutkat/L). Alkaline phosphatase and bilirubin levels
were normal. Hepatitis A and B serologies were negative. Amy-
lase, lipase, electrolytes, blood urea nitrogen, and creatinine lev-
els were normal. He was removed from work and his symptoms
improved. Ten days later his AST level was 1.03 jukat/L and
ALT level was 4.37 jukat/L. The patient has been lost to fur-
ther follow-up.
A previously healthy 43-year-old Hispanic man was referred
after we obtained the results of his screening liver function tests,
which included AST level, 8.88 jukat/L; ALT level, 8.80 jukat/
L; total bilirubin level, 148 fimol/L (normal, less than 26
u,mol/L); direct bilirubin level, 92 /xmol/L (normal, less than
5.1 jumol/L); alkaline phosphatase level, 3.67 jukat/L (normal,
0.16 to 1.16 jmkat/L). He had worked at the plant for 4 months
as a machine operator and helper. He had complained of ab-
dominal pain, nausea, and jaundice for 1 to 2 weeks previously,
but had not sought medical attention. He drank 6 to 12 cans of
beer a night. He had no history of alcohol related medical prob-
lems, intravenous drug use, or blood transfusions.
Figure 6. Liver biopsy specimen of Patient 6 shows moderate stea-
tosis in periportal hepatocytes in both microvesicular (arrow) and
macrovesicular form. Other hepatocytes show nuclear pleomor-
phism and binucleation, features of regenerative activity. (Hema-
toxylin and eosin; original magnification x 100.)
On physical examination the patient was jaundiced. There
were no stigmata of chronic alcohol use. Abdominal examina-
tion showed a mildly enlarged nontender liver. Repeat laborato-
ry values several days after the initial tests included AST level,
11.97 u,kat/L; and ALT level, 13.0 u,kat/L; an abdominal echo
showed a diffusely echogenic liver; the size was within normal
limits. Hepatitis A IgM antibody and hepatitis B surface anti-
gen and antibody were negative.
The patient was removed from his workplace and advised to
abstain from alcohol; his symptoms resolved. Two weeks later
his ALT level was 2.49 fikat/L, AST level was 1.51 /xkat/L;
and total bilirubin level was 54.74 u,mol/L. By 2-month follow-
up his transaminase and bilirubin levels had returned to nor-
A previously healthy 30-year-old Hispanic man was also re-
ferred based on the results of screening tests, which were AST
level, 1.48 /xkat/L; ALT level, 2.62 u,kat/L; bilirubin and alka-
line phosphatase levels were normal. He had worked at the
company for 6 weeks before having his blood drawn. He com-
plained of occasional abdominal pain and dizziness. He drank a
few beers on weekends only and had no history of intravenous
drug use, blood transfusions, or medications. The patient was
transferred to a nonproduction job, packing the finished rolls of
cloth, but on weekends he also worked on one of the coating
machines. Two weeks later his AST level was 2.49 jukat/L and
ALT level was 9.96 u,kat/L. He was removed from work. One
month later his AST level was 1.00 jmkat/L and ALT level was
4.83 /ikat/L, and he had a liver biopsy done. The biopsy speci-
men showed evidence of a resolving mild toxic injury to the
liver with mild centrilobular microvesicular steatosis and regen-
erative changes, identical to that of Patient 1. Five months after
removal from work his AST and ALT levels had returned to
A previously healthy 18-year-old Hispanic man started work
at the company after the screening liver function tests had been
drawn. After 2 weeks at work he noted decreased appetite and
abdominal pain. After 6 weeks at work laboratory values
showed an AST level of 5.20 jmkat/L and ALT level of 9.66
u,kat/L; bilirubin and alkaline phosphatase levels were normal.
Two weeks later he was evaluated in the clinic. The patient had
previously worked at the same company for 4 months and had
left because of these same symptoms, which resolved after he
Redlichetal. • Exposure to Dimethylformamide
Page 7
left the company. The patient had no history of significant alco-
hol use, blood transfusions, or intravenous drug use. Repeat
laboratory values included AST and ALT levels of 2.94 jukat/L
and 11.89 jukat/L, respectively. Hepatitis A and B serologies
were negative. Five weeks after removal from work his ALT
level remained elevated at 10.91 jxkat/L, and his AST level was
3.15 jukat/L. He had a liver biopsy done that showed a chronic
inflammatory infiltrate and nonspecific pattern of spotty lobular
necrosis evidenced by scattered acidophilic bodies and aggre-
gates of mononuclear inflammatory cells within sinusoids and
replacing individual hepatocytes. An abdominal echo was unre-
markable. Viral serologies for Epstein-Barr virus, cytomegalovi-
rus, and toxoplasma were negative for any active infections.
Seven months after removal from work his symptoms had im-
proved and his ALT level had dropped to 2.31 jukat/L with an
AST level of 0.81 /xkat/L.
A 37-year-old Hispanic man had worked for 10 years at the
company primarily as a machine operator on one of the coating
machines. He was referred based on the results of screening
liver function test that showed a normal AST level and an ALT
level of 1.41 jukat/L. He noted symptoms of alcohol intolerance
and decreased appetite while at work. He had no history of
blood transfusions, obesity, or significant use of alcohol or any
medications. Three months later, during which time he had no
further known exposure to dimethylformamide, his AST level
was 0.747 /ikat/L and ALT level was 1.59 jukat/L. He had a
liver biopsy done that showed moderately severe steatosis in a
macrovesicular and microvesicular pattern with spotty necrosis
and regeneration, consistent with a toxic injury to the liver
(Figure 6).
ACKNOWLEDGMENTS: The authors thank James Revkin, M.D. and
Raul Perea-Henze, M.D. for their help with translation, and A. Brian West,
M.B., M.C.R. Path, for his assistance with the photomicrographs.
Grant support: in part by a National Institute of Environmental Health
Sciences Clinical Investigator Award ES-00131. Carrie A. Redlich, M.D.
was a Charles A. Dana Foundation fellow in Occupational Medicine during
the conduct of this work. Mark R. Cullen, M.D. is a Henry J. Kaiser Family
Foundation faculty scholar in general internal medicine.
• Requests for reprints should be addressed to Carrie A. Redlich, M.D.;
Department of Respiratory Diseases, University of Washington, BB-1253
Health Science Bldg., Rm. 12; Seattle, WA 98195.
1. ZIMMERMAN HJ. Hepatotoxicity:
Other Chemicals on the Liver. New York: Appleton-Century-Crofts;
2. SANTODONATO J. Monograph on human exposure to chemicals in the
workplace: dimethylformamide. Prepared for Division of Cancer Etiol-
ogy, National Cancer Institute. Center for Chemical Assessment, Syra-
cuse Research Corp. Syracuse, New York; 1985.
3. CLAYTON JW, BARNES JR, HOOD DB, SCHEPERS GWH. The inhala-
tion toxicity of dimethylformamide (DMF). Am Ind Hyg Assoc J.
4. CRAIG DK, WEIR RJ, WAGNER W, GROTH D. Subchronic inhalation
The Adverse Effects of Drugs and
toxicity of dimethylformamide in rats and mice. Drug Chem Toxicol
5. LUNDBERG I, EKDAHL M, KRONEVI T, LIDUMS V, LUNDBERG S. Rel-
ative hepatotoxicity of some industrial solvents after intraperitoneal in-
jection or inhalation exposure in rats. Environ Res. 1986;40:411-20.
6. LUNDBERG I, LUNDBERG S, KRONEVI T. Some observations on dime-
thylformamide hepatotoxicity. Toxicology. 1981;22:1-7.
7. WILES JS, NARCISSE JK JR. The acute toxicity of dimethylamides in
several animal species. Am Ind Hyg Assoc J. 1971;32:539-45.
8. KENNEDY GL JR, SHERMAN H. Acute and subchronic toxicity of dime-
thylformamide and dimethylacetamide following various routes of ad-
ministration. Drug Chem Toxicol. 1986;9:147-70.
9. KENNEDY GL JR. Biological effects of acetamide, formamide, and their
monomethyl and dimethyl derivatives. CRC Crit Rev
10. MASSMANN W. Toxicological investigations on dimethylformamide. Br
J Ind Med. 1956;13:51-4.
11. TOLOT F, ARCADIO F, LENGLET JP, ROCHE L. Intoxication par la
dimethylformamide. Arch Mai Prof. 1968;29:714-7.
12. TOLOT F, DROIN M, GENEVOIS M. Intoxication par la dimethylfor-
mamide. Arch Mai Prof. 1958;19:602-6.
13. POTTER HP. Dimethylformamide-induced abdominal pain and liver in-
jury. Arch Environ Health. 1973;27:340-1.
14. REINL W, URBAN HJ. Erkrankungen Durch Dimethylformamide. Int
Archiv Gewerbepathol Gewerbehyg. 1965;21:333-46.
15. LYLE WH, SPENCE TW, MCKINNELEY WM, DUCKERS K. Dimethyl-
formamide and alcohol intolerance. Br J Ind Med. 1979;36:63-6.
16. CHI VERS CP. Disulfiram effect from inhalation of dimethylformamide
[Letter]. Lancet. 1978;1:331.
17. CHARY S. Dimethylformamide: a cause of acute pancreatitis? [Letter].
Lancet. 1974;2:356.
18. YONEMOTO J, SUZUKI S. Relation of exposure to dimethylformamide
vapor and the metabolite, methylformamide, in urine of workers. Int
Arch Occup Envir Health. 1980;46:159-65.
19. COHEN JA, KAPLAN MM. The SGOT/SGPT ratio—an indicator of
alcoholic liver disease. Dig Dis Sci. 1979;24:835-8.
20. GARDNER GH, GROVE RC, GUSTAFSON RK, et al. Studies on the
pathological histology of experimental carbon tetrachloride poisoning.
Bull Johns Hopkins Hosp. 1925;36:107-33.
21. CORNISH HH, ADEFUIN MS. Potentiation of carbon tetrachloride toxic-
ity by aliphatic alcohols. Arch Environ Health. 1967;14:447-9.
22. GROVE S, ALI-SALAD A, FARAH MA, et al. Enterically transmitted
non-A, non-B hepatitis—East Africa. MMWR. 1987;36:241-4.
23. BARNES JR, RANTA KE. The metabolism of dimethylformamide and
dimethylacetamide. Toxicol Appl Pharmacol. 1972;23:271-6.
24. BARNES JR, HENRY NW 3RD. The determination of N-methylforma-
mide and N-methylacetamide in urine. Am Ind Hyg Assoc J.
OW, CURZON EH. Identification by proton NMR of N-(hydroxyme-
thyl)-N-methylformamide as the major urinary metabolite of N,N-di-
methylformamide in mice. Life Sci. 1986;38:719-24.
26. KRIVANEK ND, MCLAUGHLIN M, FAYERWEATHER WE. Monome-
thylformamide levels in human urine after repetitive exposure to dime-
thylformamide vapor. / Occup Med. 1978;20:179-82.
27. LAUWERYS RR, KIVITS A, LHOIR M, et al. Biological surveillance of
workers exposed to dimethylformamide and the influence of skin protec-
tion on its percutaneous absorption. Int Arch Occup Environ Health.
28. MAXFIELD ME, BARNES JR, AZAR A, TROCHIMOWICZ HT. Urinary
excretion of metabolite following experimental human exposures to
DMF or to DMAC. J Occup Med. 1975;17:506-11.
6 8 6 May 1988 • Annals of Internal Medicine • Volume 108 • Number 5


text:
...Wintry mix of weather expected tonight across portions of central Kentucky...
A fast moving Alberta clipper will move from the mid-Mississippi Valley today to the central Appalachians by Thanksgiving morning. As this system passes through the region late this afternoon and tonight...it will bring a wintry mix of precipitation to much of central Kentucky.
Precipitation is expected to break out across western Kentucky this afternoon in the form of rain showers. This activity will then spread eastward into central and south-central Kentucky this evening. As the evening wears on...the rain will mix with and eventually change over to snow before diminishing toward sunrise Thursday.
Surface temperatures are expected to remain above freezing while the wintry mix falls...which will limit accumulations. However...a minor accumulation of an inch or less of slushy snow will be possible on grassy and elevated surfaces. The area most favored to see the slushy accumulations is that part of central Kentucky along and south of a line from Owensboro to Liberty Kentucky.
As the precipitation ends as flurries near dawn Thursday morning...surface temperatures will approach the freezing mark. Should this occur...some slick spots may develop on area roadways.
Stay tuned to NOAA all hazards weather radio and your local media for the latest updates on this winter weather situation.


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Dr. Stuart L. Davidson, MD
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Bar Harbor, ME 04609
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Dr. Stuart L. Davidson has been practicing medicine for 38 years. Dr. Davidson graduated from the Boston University School of Medicine in 1976. He practices medicine in Bar Harbor, ME and specializes in Orthopaedic Surgery. Dr. Davidson is affiliated with Mount Desert Island Hospital. He speaks English and French.
Gender: Male
Years in Practice: 38 Years
Languages Spoken: English, French
Medical School: Boston University School of Medicine
Graduation Date: 1976
Hospital Affiliations: Mount Desert Island Hospital
Specialties: Orthopaedic Surgery


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Opinion & Analysis
OPINION: What is the loneliest job in the world?
Could it be a field officer at the French-Italian Concordia research station in Antarctica, built on an ice plateau 3200 metres, and one of the remotest places on earth? Or perhaps a scientist at the Northeast Science Station in Siberia, Russia?
Sometimes I think the prize for lonely jobs could go to the average sales person for a Kiwi exporter, especially in sectors like hi-tech.
We send them off into massive foreign markets, against large and well-funded competitors, selling their wares armed with little more than a few glossy brochures and our good wishes.
Sales person appointed, job done and we can forget about that until the orders start rolling in. They are left to do everything, from introducing the company to potential customers to overcoming objections to closing the sale.
These talented, driven people achieve amazing things, selling our innovative technology to large organisations throughout the world. I am constantly astonished at the big deals these people based offshore, or even living out of suitcases, manage to put together.
Relying on this sales approach, the 'lone wolf' model, restricts our ability to grow enough technology companies of scale.
What the annual Market Measures study of sales and marketing has found is that exporters using the lone wolf model face several growth challenges.
Their cost of sales is high relative to the value of the product they are selling, and this stays relatively constant.
A symptom of this will often be long sales cycles - the average time it takes to secure a sale - which hits these small to medium-sized companies with inconsistent cash flow.
They also become very vulnerable to the quality of their sales staff. If they can't recruit and retain star performers, it has a massive effect on the company's revenue. Company growth tends to be directly correlated with the number of quality sales staff they can recruit.
Distributors can also be hard to engage with effectively, as the company isn't attuned enough to their target markets to work effectively with local partners.
How can you make the sales person's job a little less lonely, more like hunting in a wolf pack than alone, and therefore more cost-effective for the organisation?
It takes intensity, clarity and a programme.
Intensity means having the courage to focus on a very specific market opportunity or set of opportunities. That makes it easier for you to raise awareness of your brand, so when a sales person calls, the prospect already has some understanding of it.
Clarity means being able to articulate a clear and compelling offer to the defined set of prospective customers - the market. That is, being able to show potential customers very strongly how your product will benefit them, and how it has benefited similar organisations in their market.
Most importantly, it takes a programme to create a wolf pack approach to sales. That means supporting your poor, lonely sales people by implementing a set of tactics that 'warms up' your target market.
If this programme is working well, when a sales person calls on a potential customer, part of their job is already done.
The prospect knows about your product and the potential benefits it offers.
You can use a wide array of tactics to achieve this, from direct mail to tradeshows to publicity to online marketing.
Given that people in virtually any market for any product are doing their purchase research online, you need to especially consider online tactics, including your website, email and social media.
Here's an example of the wolf pack approach.
Imagine you are selling cattle breed management software and have done the research to determine there are 7083 registered beef farms in the US state of Montana, with a need to use software to manage the quality of their herds.
You don't want an expensive sales person spending their time calling up all 7083 farmers, given a good number may not be interested at all, or at least not right now. Having the right marketing programme in place helps build awareness and pull in those with an immediate interest, so you can deploy your talented sales resource to close the deal.
According to the research, companies that apply this wolf pack approach, where the sales person is adequately supported, gain some important advantages.
Sales people aren't just left to it. Other parts of the company support them, enabling them to focus on closing deals.
As prospects come to sales 'warmed up', the sales process is more efficient, lowering the average cost of sale. Lead times drop, and cashflow smoothes out.
Most importantly, growth isn't simply dictated by how many talented sales people you can attract. Scale can be achieved. And the poor old sales person feels more like part of a team, rather than a scientist in Siberia.
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text:
Owl Ninja posted:
Recall that humans are jelly-filled pastries. The jelly is essential to sustain human life. Replenish your reserves! Drink the human's jelly before it is wasted.
Consuming jelly.
_Sexy_Pants_ posted:
You have seen the large yellow object move quickly about the area. When the jelly ceases to flow, attempt to tame this beast of burden!
Jelly has ceased to flow. I have entered the vehicle.
Justin Credible posted:
The interface the human parasite was using to move the work animal must be accessible to you. See if there is some where you can input Microsoft. Search for any controls and activate them one by one, in turn.
I believe I have engaged light speed drive.
Justin Credible posted:
Find the velocitator and engage it. Do not be concerned with obstacles. Any vehicle advanced enough for light speed surely has the molecular realignment capacator installed and will pass through solid matter effortlessly.
Throttle engaged.
The human vehicle is moving at a high rate of speed.
cyclonic posted:
The human on top of the vehicle must be causing drag. Stop the vehicle quickly in an attempt to dislodge him.
tastysoup posted:
Do you see any people outside? Scream out the window and ask them where Microsoft is. If they don't tell you hit them with your vehicle.
You Will Read This Headline. Then You'll Laugh. Then You'll Realize You Were Wrong All Along.
'We're going to be in trouble!' Little Sister wailed, clutching her favorite book to her chest and sobbing. 'This isn't fun like a story anymore!' But Big Sister was not listening, she was thinking. She grabbed Little Sister's book from her and ran into town, yelling 'Help! A book made me and my sister hurt someone!'
Val Kilmer lures 6 morons into the ultimate death schvitz to prove global warming is real.
The Goons have already started their preparations, because that pitch isn't going to carpet itself!
When it comes to gaming laptops, you can never have too many LEDs or too much bad taste.
The Comedy Goldmine examines the funniest and most creative threads from the Something Awful Forums. Although the Comedy Goldmine has changed authors many times over the years, its focus on the Something Awful Forums is still the same. Includes hilarious Photoshops, amusing work stories, parodies, and other types of oddball humor.
Copyright ©2014 Rich "Lowtax" Kyanka & Something Awful LLC.


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". . . See How The Army's Toughest Soldiers Get Made"
Also see...
After his 20-year old son overdosed on drugs, Mike Stollings decided to post a photo of his body at the funeral home on Facebook out of grief and guilt. The...Read More
Craig Newmark
Associate Professor of Economics, North Carolina State Univ.
Related Articles
Narrative and the Memory of War
"It is a measure of the power of narrative that we publicly grieve more for the deaths of our enemies than those of our allies in a war that is now fading quickly from human memory," the blogger Tigerhawk writes. On both the European and Pacific theaters of World War II, Hollywood and the rest of the left have certainly been doing their part in recent years.
U.S. Releases Brutal Anti-ISIS Video, Done as a Mock Recruiting Film [GRAPHIC VIDEO]
The US government is trying its own hand at video propaganda in this war against the Islamist group known as
What's not to like about the Blue Angels?
You know it's been a good evening when Mom, Dad, and the kids all leave a party ebullient. The party


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Classes can be any day of the week (even weekends) in the morning, afternoon or evening.
In certain circumstances, if your home or office is not suitable, you can take your classes at the trainer's office. All course materials are provided.
We will be happy to offer a free language consultancy before the start of your language training course. This normally takes the form of a telephone conversation in which your specific language training requirements are discussed. We talk about the business situations in which you might be required to use your new language skills, and what work-specific terminology you would like to be able to use in the target language. We can also advise on the best method of learning for you to achieve your goals, and then design a language training course which will enable you to achieve them.
My tutor constantly sought (and provided) feedback and made slight adjustments based on my preferences or based on her observations of my strengths and weaknesses.
Our Korean courses in Boston are taught on a one-on-one basis and will help you improve your business communication skills immensely. Your progress from the basics to more advanced matters will depend on various factors, such as how much you know before you begin and your speed of learning. At the end of the course learners will be comfortable communicating via telephone and email in Korean. Of course, it is then up to you to decide how you will use these skills to advance your career.
Learning a second language can be fun as well as educational with our Korean courses in Boston. Of course, the basics come first but after that the course is all about covering your requirements and giving you the best possible start in the Korean language. Ideal for those studying for an examination in Korean as well as people heading abroad for a variety of reasons, our general one-to-one courses cover student-specific subjects as well as survival Korean, allowing the user to communicate proficiently in Korean speaking nations.
Anyone who is looking for Korean courses in Boston for a small group can arrange this with us too. Our Two-to-One Korean courses and In-Company Small Group Korean courses let students with the same needs study together. The students need to be at the same level and be in the same place at the same time for the Korean classes. They should also all be booked together This type of approach is ideal for up to 8 Korean students. Bigger groups than this can still be catered for, with a maximum of 12 able to take part in an In-Company Taster Korean course.
By tracing the origins or etymology of words you can often uncover interesting stories. Many words in English, for example, come from other languages, and some took a very meandering path to get t...
» Read More
Who's the best language teacher to help you reach fluency? Our expert explores: http://t.co/seAZxDk9nc


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Game Questions & Answers (Q&A) service lets you ask questions about video games for game consoles or PC games. So ask your Pokemon X question for 3DS and get answers from real gamers or answer questions and share your insights and experience with the rest of the gaming community.
- Developer: Game Freak
- Publisher: Nintendo
- Genre: Role-Playing Console-style RPG
- Release Date: Oct 12, 2013
- ESRB: Everyone
Question & Answers
Looker side quest
How do you beat the part where the gang members join team flare and you have to look for something were is that something?
Answer from: Suprnova
Keep pressing A while looking at the bookshelves. You will find several books which will be read. Once thats over, talk to the guy in the middle of the room. Hope I Helped!
Answer from: SPOILER!
Go back to the elevator and follow the guy that goes into the doorway, then go out of Lysandyre Labs into the Boutiqe Couture and buy clothes, then Emma will Holo-Cast you to go back there, and yoy will be beaten surely by the green haired guy because hes got an undefeatable pokemon. you will wake up from blacking out in the Looker Bereau and they will be talking about you. thats all i can tell you right now, sorry.
Answer from: SeeMeDance 8B
@SPOILER: I think you've got a vivid imagination there. Just to clarify, SPOILER! is not telling the truth. You have to go to the back of the room and keep searching the bookshelves from back to front by pressing A while facing them. HOPE I HELPED! 8B
Unanswered Questions
From: Fennekin
Posted on: 11-08-2014
From: Raikouandpika
Posted on: 07-22-2014
Pokemon X - Nontelop Trailer
- Apr 9, 2013, Views: 89
Pokemon X - Mega Pokemon Revealed Trailer
- Nov 20, 2013, Views: 88
- Maru Goukaku! FP3-Kyuu Heisei 26-27 Nendo-Han, (3DS)
- Maru Goukaku! FP2-Kyuu Heisei 26-27 Nendo-Han, (3DS)
- Persona Q: Shadow Of The Labyrinth, (3DS)
- Pokemon Alpha Sapphire, (3DS)
- Pokemon Omega Ruby, (3DS)
- Fujiko F. Fujio Characters Daishuugou! SF Dotabata Party!, (3DS)
- MahoCole: Mahou * Idol Collection, (3DS)
- Dolly Kanon Dokidoki Tokimeki Himitsu No Ongaku Katsudou Start Desu!!, (3DS)
- Anpanman To Touch De Wakuwaku Training, (3DS)
- Sumikko Gurashi: Koko Ga Ochitsukundesu, (3DS)
- Pokemon Omega Ruby, (3DS)
- Persona Q: Shadow Of The Labyrinth, (3DS)
- Pokemon Alpha Sapphire, (3DS)
- Style Savvy: Trendsetters, (3DS)
- Harvest Moon 3D: A New Beginning, (3DS)
- Nintendogs + Cats: French Bulldog And New Friends, (3DS)
- New Super Mario Bros. 2, (3DS)
- Animal Crossing: New Leaf, (3DS)
- LEGO City Undercover, (3DS)
- Ultimate NES Remix, (3DS)
- Kim Kardashian: Hollywood - Gameplay, (iPhone-iPod)
- Episode: Choose Your Story - Gameplay, (iPhone-iPod)
- How To Train Your Dragon 2 - Ready To Fly Trailer, (Wii)
- The Settlers - Kingdoms Of Anteria - Announcement Trailer, (PC)
- Entwined - Quick Look Trailer, (PS3)
- Blue Estate - Official Launch Trailer, (PS4)
- Goat Commando 3D Simulator - Gameplay, (iPhone-iPod)
- Munin - Official Launch Trailer, (iPad)


text:
Book your room at Bleu Emeraude Residence
Studio, 1 Double BedMax Occupancy: 2 guests (up to 1 child, 1 infant)
Suite, 2 BedroomsMax Occupancy: 6 guests (up to 5 children, 2 infants)
Suite, 1 BedroomMax Occupancy: 4 guests (up to 3 children, 2 infants)
Beachfront hotel for sun and fun
This Grand Case hotel is set on the beach a short distance from Happy Bay Beach, Anse Marcel Beach, and Paradise Peak. Local attractions also include Orient Bay Beach and Pinel Beach.
Hotel Features
Amenities at Bleu Emeraude Residence include free self parking.
Room Amenities
Flat-screen televisions come with satellite channels. Guestrooms also feature kitchens, complimentary wireless Internet access, and washers/dryers.Information missing or incorrect? Tell us!
Bleu Emeraude Residence
Hotel Amenities
A complimentary breakfast is offered each morning. Complimentary self parking is available on site.
- Free breakfast
- Elevator/lift
- Front desk (limited hours)
- Total number of rooms - 11
- Number of floors - 3
- Free self parking
- Year Built 2008
- Number of buildings/towers - 1
Family Friendly Amenities
- Free Wi-Fi
- Kitchen
- In-room childcare (surcharge)
- Separate dining area
- Washer/dryer
- Refrigerator
- Microwave
- DVD player
Room Amenities
- DVD player
- Balcony
- Air conditioning
- Refrigerator
- Coffee/tea maker
- Kitchen
- Shower only
- Hair dryer
- Cribs/infant beds available
- Complimentary bottled water
- Microwave
- Cookware, dishware, and utensils
- Washer/dryer
- Separate dining area
- Dishwasher
- Stovetop
- Satellite TV service
- Free Wi-Fi
- Daily housekeeping
- In-room massage available
- In-room childcare (surcharge)
- Iron/ironing board
- Flat-panel TV
- In-room safe (laptop compatible)
- iPod docking station
Where to Eat
A complimentary breakfast is served each morning between 8 AM and 10 AM.
To make requests for specific accessibility needs, complete the "Special or Accessibility Requests" section of "Trip Preferences" when you book your hotel.
- In-room accessibility
Hotel Policies
Check-in time ends at 7 PM
Check-in time starts at 4 PM
Special check-in instructions:
Check-out time is 11:30 AM
Payment types
You need to know
Extra-person charges may apply and vary depending on hotel policy.
Government-issued photo identification and a credit card or cash deposit are required at check-in for incidental charges.
Special requests are subject to availability upon check-in and may incur additional charges. Special requests cannot be guaranteed.
- Resort fee
We should mention
A resort fee is included in the total price displayed.


text:
9-(4-Dimethylaminophenyl)benzo[b]quinolizinium: A Near-Infrared Fluorophore for the Multicolor Analysis of Proteins and Nucleic Acids in Living Cells
Article first published online: 22 MAY 2013
DOI: 10.1002/chem.201301164
Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chemistry - A European Journal
Volume 19, Issue 27, pages 8736–8741, July 1, 2013
Additional Information
How to Cite
Bortolozzi, R., Ihmels, H., Thomas, L., Tian, M. and Viola, G. (2013), 9-(4-Dimethylaminophenyl)benzo[b]quinolizinium: A Near-Infrared Fluorophore for the Multicolor Analysis of Proteins and Nucleic Acids in Living Cells. Chem. Eur. J., 19: 8736–8741. doi: 10.1002/chem.201301164
Publication History
- Issue published online: 21 JUN 2013
- Article first published online: 22 MAY 2013
- Manuscript Received: 26 MAR 2013
Funded by
- Deutsche Forschungsgemeinschaft. Grant Number: FOR516
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text:
Forum planned after alleged assault at Ohio U.
A southeastern Ohio university is hosting a forum after an alleged sexual assault on a public street brought unwanted international attention in recent weeks.
Organizers say the event Thursday afternoon at Ohio University in Athens will be a dialogue about sexual assault, consent and bystander intervention.
The forum comes after a sex act on an uptown street was recorded by witnesses on cellphones cameras on Oct. 12 and widely circulated on the Internet. Afterward the woman contacted police and said she was a victim of sexual assault.
The man and woman have been identified, and police and prosecutors have met to consider possible charges. The county prosecutor said the grand jury meeting Monday may consider evidence in the case and decide if charges should be filed.
Copyright 2013 by WLWT.com All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
Protesters arrested after march onto I-75 Tuesday evening
Bengals' Still releases statement in response to child support report
Boone Co. Sheriff's Department K-9 that bit woman put down
Cleveland releases video of 12-year-old boy shot by officer
Ferguson decision: 'Hands Up for Justice' rally held in Cincinnati


text:
Is your resume in need of a little disruption?
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Mirantis is seeking a highly strategic and tactical Product Manager to drive Mirantis? extensive and highly respected participation in the OpenStack community. You will work with the OpenStack community, partners and customers to assure that Mirantis? contributions to OpenStack10/18/2014 Mountain View, CA Save This Job
We're looking for a Senior Product Manager with experience in big data analytics, a passion for developing product strategy and roadmaps, and the versatility to work with both our engineering and marketing teams. This position is based in San Francisco and it reports to the VP of10/18/2014 San Francisco, CA Save This Job
POSITION OVERVIEW: Wealthcare Capital Management LLC, an innovative wealth management and technology company, is seeking a Product Manager who is primarily responsible for Advisor Support Coordination including account management and client servicing, and has experience working10/18/2014 Richmond, VA Save This Job
Passkey is the worldwide leader in online group reservations. The Boston-based technology company offers meeting destinations, hotels and planners a powerful web-based solution for managing group hotel reservations. The heart of the Passkey system is an innovative online booking10/17/2014 Waltham, MA Save This Job
Summary: uSamp is seeking a highly skilled Senior Demand Generation Manager. This individual will play a significant role in driving business growth through new customer acquisition and existing customer expansion, capitalizing on opportunities to raise brand awareness, and10/15/2014 Encino, CA Save This Job
Summary: A Business Development Manager's responsibilities are to aid in the management and recruitment of publishers and client relationships while sponsoring interaction to obtain projects. Assist in developing and facilitating the proposal process for specific clients/sponsors10/15/2014 Encino, CA Save This Job
Nominum has been building the backbone of the Internet for more than a decade. Nominum software is used by dozens of Internet service providers around the world, reaching more than 500 million subscribers each day, and that number is growing all the time. We?re in the process of10/15/2014 Redwood City, CA Save This Job
Department: Client Services uSamp provides progressive online and mobile technology which transforms the way clients turn online data and mobile feedback into actionable insights. With over 1 billion data points, uSamp helps businesses be better, smarter, and faster. Originally10/15/2014 Encino, CA Save This Job
Position Summary: We want high caliber sales professionals who have experience selling to and/or managing large numbers of multiple simultaneous deals for new sales and existing clients. The sales executive will represent one of the industry?s broadest product suites including10/14/2014 Des Moines, IA Save This Job
Job Description Do you want to solve problems instead of sit through meetings? Do you work better as part of a small, focused team? Do you want to feel a sense of ownership in what you do and make a real impact? So do we. We are looking for individuals who love technology,10/14/2014 Seattle, WA Save This Job
Job Description First We Feast, a James Beard Award-winning food and pop culture website owned and operated by Complex Media, is looking for a Community Manager to manage the brand?s presence across Facebook, Twitter, Instagram, and other platforms. The ideal candidate should be10/13/2014 New York, NY Save This Job
BIND Therapeutics is hiring a Clinical Trial Manager to join our growing dynamic team. Reporting to the Director of Clinical Operations, the successful candidate will be responsible for all aspects of clinical trial management including but not limited to study planning and10/12/2014 Cambridge, MA Save This Job
Summary Based in San Diego, CA, BioNano Genomics is an early commercial-phase start-up that has delivered an altogether better way of gaining a fully informed understanding of genomes. With our revolutionary new genome mapping platform, Irys, researchers can conduct unique10/12/2014 San Diego, CA Save This Job
ARGOS IS GROWING! After having met several important milestones including exciting clinical data, we are poised for new strategic objectives which will require significant new resources. Those new resources include a well-qualified Methods Validation Manager. SCOPE:Implement and10/12/2014 Durham, NC Save This Job
ROLE DESCRIPTION Are you ready to move beyond the bits and bytes of traditional tech product marketing and really make a difference? As an AtTask GTM Manager for Sales Enablement, you?ll be responsible for developing a deep understanding of the market segments and buyer personas10/12/2014 Orem, UT Save This Job
Description An Allegiance Account Development Manager (ADM) drives the growth of Allegiance?s solutions. An ADM is responsible for qualifying prospective customers and leads prior to meeting with sales executives. Tasks include following up on marketing generated leads and10/12/2014 South Jordan, UT Save This Job
The Project Manager is responsible for the delivery, cost and quality of an engine development project. The successful candidate will be required to: Manage a multi-disciplinary project team, including engineering, manufacturing, purchasing, material control, assembly and10/12/2014 San Diego, CA Save This Job
The Strategic Marketing Manager (SMM) is a new position that will report to the Sr. Director of Marketing. The ideal candidate will be a creative and strategic marketing professional who recognizes the unique attributes of Intematix and can seize opportunities to communicate10/12/2014 Fremont, CA Save This Job
If you are an independent self-motivator who can meld with various teams and be creative in problem solving, this job is for you! Apply Now A leading web-based professional education provider is seeking a motivated technical Senior Project Manager to join their Product Management10/12/2014 Hawthorne, NY Save This Job
Department: Client Services Position Overview Th Project Manager will work with others within Client Services, including Technical Support, Integration, and Management, to successfully implement the MedAptus software for various healthcare provider organizations. Essential Job10/11/2014 Boston, MA Save This Job


text: As part of our NCL cruise we stopped at Great Stirrup Cay. We rented a Cabana and were pleased to see it was stocked with water and fruit. We had a private waiter bringing us drinks. The beach was clean and the water a warm bright clear blue. This was our first time there but we are already looking to... More


text:
Spore Creature Creator contest. Check out the zoological diversity below and then vote on the Big Download site for the best one.
The grand prize winner gets a Wacom Intuos3 6x11 drawing tablet and there's great prizes for second and third place as well. Voting closes July 14, so rally the troops and make sure the best freak of nature wins.
Breaking News
Dying Light cancelled on Xbox 360, PS3
Featured Stories
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Games we love and hate
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Super Joystiq Podcast 122: Far Cry 4, GTA V, Assassin's Creed Rogue, WWE 15
Posted on Nov 21st 2014 1:30PM


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FIVE THINGS YOU DIDN'T KNOW ABOUT: Owen Comora
October 20, 2011
Do you know the senior senior bird naturalist at Myakka River State Park, Owen Comora?
Neighbors: Owen Comora
October 20, 2011
As the senior bird naturalist at Myakka River State Park, Owen Comora has devoted more than 4,000 volunteer hours to his passion.
October 20, 2011
75 — The percentage of Cardinal Mooney High School students who participate in at least one sport each school year.
Athlete of the Week: Summer Clarkson
October 20, 2011
Cardinal Mooney High School junior Summer Clarkson was among 80 riders nationally who competed in the equestrian hunter-jumper Marshall and Sterling League National Finals, in upstate New York.
October 17, 2011
We spotted this female boat-tailed grackle at the Celery Fields this morning.
PHOTO GALLERY: Rider Sandals Big Shot Volleyball Series
October 17, 2011
Teams from throughout the country competed in The Rider Sandals Big Shot Volleyball Series, which returned to Siesta Key Saturday.
PHOTO GALLERY: Welcome home, Sarasota Ballet!
October 17, 2011
Friends of the Sarasota Ballet hosted a welcome home event Monday, Oct. 17 at the FSU Center for the Performing Arts to toast the dancers of the Sarasota Ballet who danced with the Suzanne Farrell ballet at the Kennedy Center in Washington, D.C.
PHOTO GALLERY: Downtown Sarasota Art and Craft Festival
October 16, 2011
Hundreds of people came out over the weekend for the 17th Annual Downtown Sarasota Art & Craft Festival on Main Street.
PHOTO GALLERY: SHS Homecoming Weekend
October 15, 2011
Sarasota High School had their homecoming football game, Friday, Oct. 14, at Cleland Stadium and dance, Saturday, Oct. 15, at Robarts Arena.
PHOTO GALLERY: Party on the Pass
October 15, 2011
The Sarasota Chapter of Interior Design Society hosted its first "Party on the Pass" benefiting Trinity Charities at the Sarasota Sailing Squadron on Saturday, Oct. 15. Trinity Charities, Inc. is an HIV/AIDS service organization that provides services to individuals in Sarasota and Manatee counties. The bayside event included barbeque, drinks, live music from Stone Fish and a silent auction.
- Nov
22 Sarasota's Biggest One-Day Flea Market
8:30 am - 1:00 pm
- Nov
22 Kids to make free Wire Art
10:00 am - 4:00 pm
- Nov
22 Responsible Dog Owners' Day
10:00 am - 3:00 pm
- Nov
22 JDub's Barks & Brews Dog Adoption Event
12:00 pm - 4:00 pm
Cops Corner: Sarasota
Enjoy this week's edition of Cops Corner.
World on a string
The exchange of goods and chatter are the usual soundtrack for the Saturday morning Downtown Farmers Market on Orange Avenue.
Read all about it
Bookstores across the state celebrated Florida Bookstore Day Saturday. Bookstore1 held an all-ages literary party and read-a-thon for customers and members of the community.


text:
To access the full Church Times online archive please log in above with your Church Times user email & password
Posted: 02 May 2014 @ 00:15
Digging Dunelm: archaeologists working at Durham Cathedral have
found pottery that suggests there may once have been a Roman site
where the cathedral now stands. The team, which is digging in the
medieval former Great Kitchen, has discovered samian ware - glossy
red pottery from the Roman era.
Norman Emery, the cathedral's archaeologist, said: "We know
there was a site not too far away called Old Durham, on the other
side of the river, but several Roman artefacts have been found ...
Gresham CollegeFounded
Gresham Professor of Divinity
Gresham College has provided free
public lectures for over 400 years in the City of London and now
operates worldwide via the internet. Fo...
Read More
Denise Inge, who died on Easter Day this year, discovered that her home was built over a charnel house. This prompted her to write a book exploring the challenge of living well in the face of mortality
Subscribe to read more
To prevent multiple voting, we now ask readers to be logged in. This is free, quick and easy, honestly. Click here to login or registerClick here to login or register
Efforts are being made to combat corruption and sharp practice in global finance. Peter Selby has seen this at first hand
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Fri 21 Nov 14 @ 18:23This week's @churchtimes caption competition (£) http://t.co/7MLykjnfbO http://t.co/e2W7Dcex09
Fri 21 Nov 14 @ 18:11Church leaders condemn murder of American hostage http://t.co/qvOo6JbXHX