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Background Since 1998, in the countries where there is mandatory fortification of grain products with folic acid, folate deficiency has become very rare. Consequently, we decided to find out whether there is any justification for ordering folate assays for investigation of anemias. Methods We reviewed serum folate (SF) and red cell folate (RF) data at two teaching hospitals in Canada. At the Health Sciences Centre (HSC) the folate data for the year 2001 were analyzed and the medical records of those with low SF or low RF were reviewed. At St. Boniface General Hospital(SBGH)all folate data between January 1996 and Dec 31,2004 were analyzed and the medical records of all who had low RF between January 1,1999 and December 31,2004 were reviewed. Results In 2001, at HSC, 11 out of 2154(0.5%)SF were low( Conclusion In countries where there is mandatory fortification of grain products with folic acid, folate deficiency to the degree that could cause anemia is extremely rare. Ordering folate assays for investigation of anemias, in these countries, is waste of time and money. The result of these tests is more likely to mislead the physicians than to provide any useful information.

5089 Gilbert's syndrome (GS) is associated with a mild chronic unconjugated hyperbilirubinemia, due to partial deficiency of bilirubin uridine diphosphate glucuronyl transferase (UDPGT). Phenobarbital is a known inducer of hepatic UDPGT and has been used in hyperbilirubinemia of newborns. It has also been used as a test for support of the diagnosis of GS. However, because hyperbilirubinemia of GS is mild and harmless, phenobarbital is not used for treatment of hyperbilirubinemia in adults. I report a case of a 46-year-old woman who, because of having chronic hereditary hemolytic anemia and GS, had marked hyperbilirubinemia with psychosocial problems, as the result of her hyperbilirubinemia and her skin color, which responded well to chronic phenobarbital treatment. Case report- CH was diagnosed to have hereditary high phosphatidylcholine hemolytic anemia (HHPCHA) at the age of 23. She was seen again at the age of 30 because of very high serum ferritin and iron saturation which seemed disproportionally high for the degree of her mild hemolytic anemia (51Cr RBC survival T½ of 16.5 days). Further investigation revealed that she had hereditary hemochromatosis due to homozygosity for H63D HFE gene. She was started on phlebotomies initially weekly and later on every 2-3 months to control her iron overload. During the follow-up it was noted that her serum unconjugated bilirubin (SUB) was persistently much higher than is expected from her mild hemolytic anemia (up to 288 μmol/L). Since she had no abnormality of liver function tests, I suspected that she also has Gilbert's syndrome. In September 2008 her blood was sent for genetic testing which showed that she has an additional TA repeat [(TA)7/(TA)7], confirming the diagnosis of GS. On January 21, 2009 when her SUB was 149 μmol/L, she expressed concern that her friends and coworkers keep making fun of her, because of the orange color of her face and sclera. She was started on phenobarbital 30 mg daily for a month and then 60 mg daily. This therapy rapidly brought her bilirubin down and changed the color of her face to normal, making her very happy. Her SUB on February 20, March 20 and June 30, 2009 were 103, 63 and 37 μmol/L, respectively. Conclusion Gilbert's syndrome is a common hereditary disorder that can aggravate hyperbilirubinemia of chronic hemolytic anemia. However, this association is often unrecognized, because many physicians attribute the hyperbilirubinemia to hemolysis and do not look for associated GS. In chronic hemolytic anemias, if hyperbilirubinemia is more than expected, the possibility of an associated GS should be considered. If such association exists, small daily doses of phenobarbital can markedly reduce this hyperbilirubinemia and improve the psychosocial effects of hyperbilirubinemia. Furthermore, marked reduction of bilirubin, following the therapeutic trial of Phenobarbital, will confirm the association of GS with hemolytic anemia. Disclosures No relevant conflicts of interest to declare.

A man born in 1951 underwent a bone marrow examination, on May 10, 1991, for investigation of his pancytopenia. The bone marrow slides were sent to me for interpretation. I made the diagnosis of myelodysplasia (refractory anemia without excess blast). The patient was subsequently referred to a hematologist in another hospital for further investigation and management. A repeat bone marrow aspiration and biopsy on May 30, 1991 again demonstrated myelodysplasia. Bone marrow biopsy, flow cytometry and cytogenetic studies were normal. His Hgb was 124 G/L, WBC 2.2 and platelet (Plt) 151 × 10e9/L. CT scan of the chest and abdomen showed mediastinal and retroperitoneal lymphadenopathy and marked splenomegaly suggestive of lymphoma. There was no symptoms suggestive of lymphoma. The patient was followed without any therapy. In March 2002 he was referred to an immunologist because of frequent episodes of pneumonias. He was found to have panhypogammaglobulinemia. The immunologist recommended monthly I V immunoglobulin(IgG). Initially the patient refused this treatment; but subsequently he agreed and he was sent to me on November 3, 2003 for consideration of monthly IV IgG infusion. Hgb 125 g/L, WBC 2.5 and Plt 112 ×10e9/L.IgG 2.31, IgA Date IgG (G/L) IgA (G/L) IgM (G/L) Hgb (G/L) WBC X10e9/L Plt ×10e9/L 20/12/01 2.7

A 62-year-old female was referred to me, on January 23, 2004, because of leukocyosis. She was obese with the weight of 141.5 Kg. Her WBC was 37.6 x 10e9/L with neutrophillia. The findings on examination of her blood smear were strongly suggestive of CML. Her blood was sent for BCR-ABL detection and bone marrow aspirate was sent for cytogenetic studies. No therapy was given while awaiting the result of these tests. On March 12, 2004, Hgb was 144 G/L, platelet count 318 x 10e9/L, WBC 66.5 x10e9/L. WBC differential showed 57% neutrophils, 11% bands, 4% metamyelocytes, 8% myelocytes, 2% promyelocytes.... BCR-ABL fusion gene product had been detected in her peripheral blood; and cytogenetic studies had demonstrated Philadelphia (Ph) chromosome in all of the cells examined. The diagnosis of Ph + CML in chronic phase with low Sokal score was made. Despite her morbid obesity, she was started on standard recommended dose of imatinib 400 mg daily. After 6 weeks of therapy her WBC was 9.5 x 10e9/L with normal WBC differential and she was in complete hematological remission. When she was tested after 7 months of therapy, there was a three log decrease in BCR-ABL fusion gene. BCR-ABL fusion gene was undetectable in the next study that was done at 16 months of therapy. Since then, she has remained in complete molecular remission, with no detectable BCR-ABL fusion gene (last test 3 years after starting therapy), on imatinib 200 mg daily. The only repeat cytogenetic study of the bone marrow carried out 2 years after starting therapy showed normal karyotype and no Ph + chromosome. Discussion: There is a marked difference in active transport of imatinib in and out of the cells and sensitivity of Ph + CML cells of different patients to imatinib. In the initial trials the dose of 400 mg daily was selected because, in most of the patients, irrespective of their weight, this dose was associated with adequate uptake of imatinib which could inhibit cellularr tyrosin kinase activity. Furthermore, in the majority of the cases, the side effects of this dose of imatinib were tolerable. However, this drug is very expensive and because it has to be taken for many years, it creates a major financial burden for the patient or for the health care system. The question then arises whether it is justified to give unnecessary higher doses of imatinib that are needed, to many patients in order to produce higher rate of remission in patients with CML. In the case cited above, considering her weight, she was given a dose of imatinib which would be the equivalent of 200 mg daily for average weight patients. Nevertheless, she responded promptly to such a relatively low dose of imatinib without experiencing any side effects attributed to imatinib. Carella and Lerma (Ann Hematol 2007: June 19, Epub ahead of print) recently reported the outcome of four CML patients who were imatinib-intolerant but who had undetectable residual disease. The imatinib dose in these patients was reduced to 200 mg daily. All four patients have remained in complete remission with undetectable residual disease from 4 to 37 months. Conclusion: Until an in vitro test of imatinib sensitivity of Ph + cells becomes available, it seems reasonable that an average weight patient with CML in chronic phase and low Sokal score be started on imatinib 200 mg daily initially. Only if such patient fails to show a complete hematological response within three months, should the dose of imatinib be increased to 400 mg daily.

A Caucasian female, born in 1941, was first seen in November 2002 because of tiredness, weight loss and splenomegaly. She was taking glyburide, procylidine and venlafaxine for diabetes, parkinsonism and depression. Physical examination, revealed marked splenomegaly but no lymphadenopathy. Flowcytometry of peripheral blood showed a monoclonal B cell lymphoproliferative disorder consistent with marginal zone lymphoma. She was treated with chlorambucil 6 mg daily and prednisone 25 mg daily. She responded well to therapy. Chemotherapy was discontinued in December 2003. In April 2005 she was admitted to the hospital with pneumonia. She had pancytopenia and marked splenomegaly. Bone marrow apirate showed infiltration with marginal zone lymphoma cells. She was prescribed Chlorambucil 6 mg daily for management of her recurrent lymphoma. She took her first 6 mg of Chlorambucil at 8:00 PM of May 18, 2005 and woke up around 5:30 AM with grossly swollen tongue. She was brough to Emergency ward at 06:45 hr with grossly swollen, tender tongue protrudinng form her widely opened mouth. Angioedema of the tongue was diagnosed and she was given epinephrin, IV Benadryl, Solumedrol and morphine. By 10:00 hr, she was in moderate respiratory distress. She was taken to OR at 10:20 for urgent intubation or tracheotomy. Endoscopy revealed ++ oropharyngeal and supraglotic edema. A nasotracheal tube was inserted at 11:00 hr. The picture included was taken one hour after intubation.(16 hrs after taking chlorambucil). She was given Solumedrol 125 mg IV Q 12 hr. By 24 hours after intubation her tongue had receded into her mouth and she was extubated. Her serum C1 inhibitor was 0.13 g/L (normal 0.15–0.35) and functional C1 esterase inhibitor was 87% (normal >67%). Immunoglobulines, C3 & C4 were normal. Her lymphoma was treated with 6 courses of R-CVP regimen. She has not received any more chlorambucil and she has not had any more angioedema or anaphylactic reaction of any kind. In May 2005 her C1 inhibitor was 0.38 g/L and functional C1 esterase inhibitor was 96%. Discussion: on the day before experiencing angioedema of the tongue, she had not taken any unusual food or any other new medication. The time sequence and subsequent course of this case strongly suggest that the angioedema of the tongue was due to Chlorambucil. The literature does not show any report of chlorambucil induced angioedema. However, angioedema is listed as one of the adverse reactions of Chlorambuci both in AHFS Drug Information and in Compendium of Pharmaceuticals and Specialities. Following communication with GlaskoSmithKline, the manufacturer of Chlorambucil, I was told that, they are not aware of any published report, but they have reports of angioedema induced by Chlorambucil in their file. I was told that they are not in position to reveal the number of such reactions. Figure Figure

Since 1999, due to mandatory fortification of grain products with folic acid, folate deficiency has become very rare. We elected to find out whether there is still any justification in ordering folate assays in medical practice. Methods: All the Red cell folates (RFA) at St. Boniface General Hospital (SBGH) for the period of January 1, 1996–Dec 31, 2001 and all of serum folates (SFA) and RFAs at Health Sciences Centre (HSC) for the period of January 1-December 31, 2001 were reviewed. The medical records of all patients who had low SFA or RFA were reviewed to find the cause of low folate results. At SBGH L. Casei microbiological assay and at HSC, a competitive binding assay of folates was used. Results: Among 2153 SFAs performed at HSC 10 (0.46%) were below normal. All 10 were anemic but their SFAs were not as low as those seen in folate deficiency anemia. Only one case had a high mean corpuscular volume (MCV). This patient had ethanol induced pancreatitis and his macrocytosis was considered to be due to ethanol abuse. Two patients had celiac disease. In the other seven patients there was no evidence of folate deficiency anemia and no explanation could be found from the review of their medical records as to why their SFAs were low. Among 560 RFAs performed at HSC, 4 patients (0.7%) had low RFAs. In one case, the low RFA was due to B12 deficiency. The second case was the same patient with ethanol induced pancreatitis who also had low SFA. The other two had celiac disease. AT SBGH, there was a progressive increase in mean RFA and a decrease in percentage of those with low RFA during each year in the period between 1996 and 2001. In 1996 the mean RFA was 509 nmol/L and 95 out of 511 (18.5%) had low RFA. During the 3 year period of 1999–2001, the mean RFA was 947 nmol/L and 19 out of 991(1.6%) RFAs were low. Of these 19 patients, 9 were ethanol abusers with alcoholic liver disease, 7 had celiac disease, two had low RFA due to severe B12 deficiency and one was an AIDS patient who was admitted because of extreme malnutrition and had a low RFA, a low serum B12 (SB12) and a low serum ferritin. Of 7 patients with celiac disease, only one had had a high MCV. Discussion: There are generally three reasons why physicians order folate assays. The most common reason is to detect folate deficiency as the cause of anemia. Our study shows that folate deficiency is now very rare. In none of the patients with low SFA or RFA could we attribute the anemia to folate deficiency. The second reason is for investigation of hyperhomocysteinemia. Since folate deficiency is now very rare and management of hyperhomocysteinemia is the same whether SFA or RFA are low or normal, having SFA or RFA result would not change the patient’s management. The third reason for ordering RFA is for screening for malabsorption syndrome. During 30 months period of July 1, 1999–December 31, 2001, the search of the Laboratory Information System at SBGH, revealed 29 patients with serological evidence of celiac disease, who also had SFA or RFA results. Of these 29, five had low SFAs and two had low RFAs. Conclusion: We find very little support for the need to order serum or red cell folate in medical practice. In those rare occasions, when folate deficiency is suspected by the patient’s history or laboratory findings, it is simpler and more economical to treat the patient with folic acid (as long as one makes sure the SB12 is normal) than ordering folate assays and waiting for the results that most likely going to be normal.

In the past, before immunological tests for celiac disease became available, many authors advocated the use of red cell folate (RFA) as a screening test for celiac disease. That is, if the red cell folate were normal, then celiac disease was considered very unlikely. Low red cell folate was found in all 24 cases of celiac disease reported by Hoffbrand et al (J Clin Pathol1966;19:17–28). Since Patients with celiac disease and tropical sprue absorb the folic acid used in the fortification of grain products much better than folate polyglutamates present in food, I decided to investigate whether serum or red cell folate is still useful for screening malabsorption syndrome. Methods: Serum folate (SFA) and red cell folate at St. Boniface General Hospital (SBGH) were determined by L. Casei microbilogical assay. During the 30-month period of July 1,1999 – Dec 31, 2001, the search of Laboratory Information System (LIS) at SBGH, revealed 29 patients with strong laboratory evidence of celiac disease (strongly positive gliadin antibody with positive endomysial and or t-transglutaminase antibodies) who also had SFA or RFA results. LIS was searched for the results of complete blood count (CBC), SFA, RFA, serum ferritin (SFer) and serum B12 (SB12). Results: Five out of 29 patients (17.2%) with laboratory evidence of celiac disease had low SFA. Of these 5 patients with low SFA, 4 also had RFA. Only one of these 4 with low SFA had a low RFA. Eleven of the 29 patients also had RFA and only 2 of these 11 (18%) had low RFA. One of the two with low RFA had a normal SFA; and the other had a low SFA, a low SB12 and a low SFer. Twelve of 29 (41.3%) with celiac disease had low SFer and 6 of 29 (20.6%) had low SB12. Four out of 29 (13.8%) had high mean corpuscular volume (MCV)(> 98 fL). All of the four with high MCV had normal RFA, but had low SB12, indicating that macrocytosis in these 4 cases was due to B12 deficiency. Ten out of 12 with low serum ferritin had low MCV ( Discussion: The mandated fortification of grain products in USA and Canada (0.14 mg of folic acid per 100 g of grain) was estimated to add about 0.1 mg of folic acid to the daily folate intake of the average adult. However, some studies have shown that the actual increase in daily folate intake, through folic acid fortification, is about 0.2 mg (J Nutr2002;132:2792–8 and Am J Clin Nutr2003;77:221–5). Patients with celiac disease or tropical sprue can absorb this folic acid much better than the folate polyglutamates present in food. Sheehy et al (Blood1961;18:623–36) have demonstrated that many patients with tropical sprue who had developed folate deficiency megaloblastic anemia, despite consuming more than 1 mg of food folates daily, responded to as little as 0.025 mg of folic acid daily. It is for this reason than most of our celiac patients had normal serum folate but were either iron deficient or B12 deficient. In the past, B12 deficiency was considered to be uncommon in untreated adults with celiac disease. Conclusion: As the result of fortification of grain products with folic acid, red cell folate is no longer a useful test as a screening test for malabsorption syndrome. Now, as our data demonstrate, B12 deficiency is more common than folate deficiency in adults with untreated celiac disease. A patient with celiac disease and macrocytic anemia is more likely to be B12 deficient than folate deficient.

Isolated bilateral ovarian lymphoma is extremely rare. Those reported are generally due to aggressive lymphoma and are associated with a poor outcome. We present a case of low grade abdominal lymphoma which had been treated with bowel resection and chemotherapy. The patient subsequently developed recurrence of lymphoma in both ovaries and underwent bilateral oophorectomy. She has remained free of lymphoma for 10 years without any therapy for lymphoma. Case report: A Caucasian female was born in 1940. In July 1985, she underwent a surgical removal of a large mesenteric mass and a 72 cm length of small bowel. The pathology report indicated the involvement of small bowel, mesenteric nodes and mesenteric fat with: Diffuse poorly differentiated lymphocytic lymphoma (Rappoport), malignant lymphoma, follicular and diffuse, predominantly small cleave cells with focal sclerosis (working formulation). She was treated with chlorambucil until July 1992 when because of leucopenia, chemotherapy was discontinued. CT scan of the abdomen in August 1992 was normal. In August 1995, she presented with acute abdominal pain. She underwent a resection of both ovaries, of the Fallopian tubes and of the uterus. The pathology report indicated that both ovaries were involved with: Malignant lymphoma, lymphocytic, poorly differentiated, partly nodular. The Fallopian tubes and the uterus did not show any lymphoma. A post-operative bone marrow biopsy and a CT of the chest and abdomen did not show any abnormality. Because there was no evidence of residual lymphoma, no therapy was offered after the operation. She has remained disease free 10 years after resection of the ovaries. The CT scan of the chest and abdomen in May 2004 were normal. Because of the unusual course of the disease and long-term disease free survival post recurrence, all of the pathological specimens were reexamined and were found to be similar microscopically and immunohistochemically. The tumors of small bowel, mesentery, omentum as well as both ovaries were reclassified in modern terminology as: Follicular lymphoma, Grade 1. The tumors have a similar appearance in that they are composed predominantly of poorly formed nodules of lymphoma with diffuse area. They have similar immunohistochemical profiles. They are faintly positive for CD20, CD22, CD10 and strongly positive for Bcl-2. Both tumors are negative for CD43 and CD45RO. Conclusion: There are two possibilities for why isolated bilateral lymphoma may have developed in this case. One is that the lymphoma of the ovaries in this case was a second lymphoma unrelated to the initial lymphoma of the bowel and mesentery. If this is the case, the identical features of the two tumors and the simultaneous appearance in both ovaries, sparing other tissues is extremely unusual. The second possibility is that the ovaries provided a sanctuary for the original lymphoma cells. The resection of the original tumor followed by chemotherapy, had destroyed all of the lymphoma cells in the other organs. But the ovaries had provided a sanctuary for the lymphoma cells, allowing them to grow locally. Removal of the ovaries provided a 10 year disease free survival.

Hereditary or congenital (TTP) is a very rare form of TTP which is associated with repeated attacks of TTP. I report a case of a 33-year old man who had had numerous attacks of TTP since birth and had evidence of mild chronic TTP between acute attacks. He had recurrent attacks despite immunosuppressive therapy, IV immunoglobuline and splenectomy. He has remained under clinical and laboratory control with regular infusion of 750 ml of cryopoor plasma every two weeks. Case history: JS, born in1972, exhibited severe neonatal jaundice associated with intravascular hemolysis and thrombocytopenia on the second day of his life. He was discharged on the 8th day with a final diagnosis of hemolytic uremic syndrome (HUS). In the first 8 years of life, he had 10 admissions to the Children’s Hospital with the diagnosis of HUS or TTP. He had been variously treated, with IV fluids, prednisone, aspirin, dipyridamole, antibiotics, and heparin + phenoxybenzamine. He had recovered from acute attacks; but, in between admissions, he had several less severe attacks of thrombocytopenis and/or hemolysis which did not require hospitalization. Between the ages of 8–17 he had had several other acute attacks of HUS for which he was generally admitted to other hospitals and treated with prednisone. He was first admitted to St. Boniface General Hospital (SBGH) in April 1992 with laboratory evidence of TTP [hemoglobin (Hgb) 95 G/L, platelet count (Plt) 17 x 10e9/L, urea = 11 mmol/L, creatinine 183 μmol/L and lactate dehydrogenase 683U/L]. He was treated with prednisone + enteric coated aspirin (ECASA) + dipyridamole and recovered from acute attacks and discharged after 5 days but he was readmitted 10 days later with another attack of TTP associated with decreased level of consciousness and left sided weakness. He responded to repeated plasmapheresis + prednisone + ECASA + dipyridamole and recovered completely. By the end of 1993, he had had 5 hospital admissions to SBGH for recurrent acute attacks of TTP and was successfully treated with repeated plasmapheresis + prednisone + ECASA. However between acute attacks he had shown evidence of mild thrombocytopenia and hemolysis. Preventive treatments with ECASA, ticlopedine, azathioprine and IV immunoglobuline had failed to prevent chronic TTP and acute attacks. In May, 1994, he underwent splenectomy for his chronic TTP, but 2 months later he had another episode of acute TTP. He was treated with plasmapheresis, prednisone and ECASA and responded well. He was then placed on regular infusion of 500 ml of cryopoor plasma (CPP) every two weeks as well as ECASA 325 mg daily. On this regimen, his Hgb, Plt and reticulocyte count remained normal. In August 1994, infusion of CPP was discontinued in order to find out whether the hematological improvement was due to the delayed effect of splenectomy or CPP infusion. Three months later he had another acute attack of TTP and he was treated with an infusion of 1500 ml of CPP daily for 4 days + prednisone and ECASA. He recovered completely. Infusions of 500 ml CPP every 2 weeks was restarted and he remained well until May 2, 1996 when he experienced another episode of acute TTP a day after he had undergone a tooth extraction. He was treated as he had been treated in the last attack with infusions of CPP and responded well. In the past 9 years he has received 750 ml of CPP infusion every two weeks and has remained in complete remission with normal platelet count, hemoglobin, reticulocyte count and haptoglonbin and he has not had any more acute attack of TTP.

Solomon[1][1] claims that many patients with clinical features suggestive of cobalamin (Cbl) deficiency who have normal serum Cbl, methylmalonic acid (MMA), and homocysteine (HCys) levels may respond to Cbl therapy, while many patients with low serum Cbl, high serum MMA, or high serum HCys levels

Background: A large clinical dataset of vitamin B12 measurements (over 12,000 patients) and Schilling tests (over 700 patients) has been assembled from participating Manitoba laboratories (1995–2000) in order to assess clinical outcomes (as defined from administrative health data) in relation to tests of cobalamin [Cbl] deficiency. In order to control for Cbl replacement, it is necessary to confirm that Cbl replacement can be accurately determined from administrative data sources such as the Drug Program Information Network (DPIN) and/or medical claims for therapeutic injections. DPIN is known to be reliable for oral prescription drugs, but parenteral Cbl may be more difficult to identify and non-prescription oral Cbl would not be recorded. We believe that the preferred route of Cbl administration in Manitoba was parenteral during 1995–2000, but this needs to be confirmed. Methods: Cases (expected to have a high likelihood for Cbl replacement) consisted of all adult hospital discharges between 1995 and 2000 with a diagnosis of pernicious anemia or other Cbl deficiency anemia (ICD-9-CM 281.0, 281.1) who survived for at least one year post-discharge without personal care home admission (n=388). Matched controls (3 controls for each case) with a low likelihood for Cbl replacement were similarly defined from hospital discharges without any ICD-9-CM neurologic or haematologic diagnosis (n=1,164). Controls were matched with cases for gender, birth year and hospitalization year. For each case and control the number of Cbl dispensations (ATC code B03BA01) and therapeutic injections (tariff code #8954) were tabulated during the first three years post-discharge. Sensitivities (fraction of cases receiving Cbl replacement) and specificities (fraction of controls not receiving Cbl replacement) were calculated for different cutoffs of Cbl dispensations, therapeutic injections and combinations according to year of diagnosis (YOD) and overall. Weighted linear regression between YOD and sensitivity was performed to look for an effect of recent oral Cbl replacement. Results: Sensitivity for the a priori operational definition (≥2 Cbl dispensations) was 0.59±0.02 with specificity 0.96±0.01. Using one or more Cbl dispensations improved sensitivity to 0.71±0.02 with similar specificity of 0.95±0.01. Therapeutic injections alone were less useful (≥1 injection sensitivity of 0.65±0.02 with specificity of 0.92±0.01, ≥2 injections sensitivity of 0.61±0.02 with specificity of 0.95±0.01). The combination that maximized sensitivity + specificity was ≥1 dispensation or ≥2 therapeutic injections (sensitivity 0.80±0.02, specificity 0.93±0.01). Sensitivity measurements did not show any significant relationship with YOD. Conclusions: The optimal definition for Cbl therapy based upon administrative health data appears to be at least one Cbl dispensation identified in the DPIN database or at least two therapeutic injections identified from medical claims. In assessing clinical outcomes in relation to Cbl testing and replacement, we propose to validate findings derived with the primary combined definition through secondary analyses using independent definitions of Cbl replacement (≥1 dispensation alone or ≥2 therapeutic injections alone). Overall sensitivity was lower than expected but may reflect that some cases are not prescribed Cbl replacement post-discharge. Sensitivity was unrelated to YOD arguing against oral Cbl replacement as the explanation.

We have studied the effect of oral contraceptives on folate metabolism, in order to test the hypothesis that folate deficiency of pregnant women may be partly due to impairment of folate metabolism. Serum folate, red cell folate, and urinary excretion of formiminoglutamic acid (FIGLU) were determined in 176 women receiving combination-type oral contraceptives (the Pill) and 140 normal control subjects. The group taking the Pill had significantly lower serum and red cell folate and higher urinary FIGLU excretion. There was a rise in serum and red cell folate and a fall of urinary FIGLU excretion within 3 months after stopping the Pill. The data demonstrate that women taking the Pill may have impaired folate metabolism and suggest that sex hormones may play a role in the development of folate deficiency in pregnancy.

Serum folate levels were serially determined in 57 premature infants from birth to 7 months of age. Twenty-four normal children and 21 normal adults served as controls. The mean value of folate activity was significantly lowest between 1 and 3 months of age. The values at 3 to 5 months of age approximated the normal controls and were coincident with the administration of adequate dietary folic acid. Twenty-eight per cent of the total number of premature infants and 68 per cent of those infants who weighed less than 1,700 grams at birth had low folate levels. Of interest is the fact that the premature infants with SFA deficiency failed to exhibit any significant hematologic responses to folinic acid. The unequivocal use of folic acid supplementation should be held in abeyance until absorption studies are completed.

The in vitro effect of heparin on platelet aggregation was studied in three groups: in 26 subjects recently treated with heparin, in 18 subjects on maintenance hemodialysis, and in 20 normal controls. With the aid of Technicon H6000, platelet counts and platelet aggregations were compared in whole blood samples collected in ethylenediaminetetraacetic acid (EDTA) and in heparinized tubes. Although there was no significant difference between platelet count of heparinized and EDTA blood in the control group, the dialysis group and the group recently treated with heparin showed significantly lower platelet counts and more platelet aggregation in heparinized tubes than in EDTA tubes. We speculate that the majority of subjects exposed to heparin develop an antibody or a proaggregator which can aggregate or agglutinate platelets in the presence of heparin and causes destruction of platelets; but only in a small percentage of subjects receiving heparin is this reaction severe enough to cause thrombocytopenia.

The variations between different lots of activated partial thromboplastin time (APTT) produced by three major North American suppliers were evaluated over the past eight years. The authors found significant variations between the heparin sensitivity of the APTT reagents produced under the same name by the same supplier. The variations were so much that, using the recommended APTT ratio or prolongation of APTT for monitoring heparin therapy, one would have achieved significantly different intensity of heparinization from year to year.

A 48-year-old man with systemic lupus erythematosus (SLE) developed disseminated intravascular coagulation (DIC) with clinical bleeding. Since no other cause for DIC could be demonstrated, he was treated with prednisone, which rapidly corrected his DIC. This case demonstrates the need for a complete hematological investigation of patients with SLE who present with hemostatic abnormalities.

Serum folate levels were determined microbiologically with Lactobacillus casei in 24 normal nonpregnant women of childbearing age and in 62 women using oral contraceptives (Ortho-Novum Ovulen C-Quens Norinyl Enovid-E) for 2 months to 5 years. The controls had mean serum folate of 6.44 ng/ml (standard deviation 2.37); the pill users had a significantly lower level of 4.46 (standard deviation 1.69 p less than .001). 19 (30%) of the pill users had folate levels lower than the lowest controls about 3 ng/ml. Addition of oral contraceptives did not inhibit growth of the test microorganism. Since folate level decreased with duration of oral contraception in some patients and levels appeared lower in patients who had used the pill for several years the authors suggest that clinicians determine folate in women who stop long-term oral contraception to plan a pregnancy.

The antileukemic agent cytarabine has recently been used to treat herpesvirus infections, but the regimens advocated for this purpose are high-dose prolonged infusions (100 mg/sq m of body surface per day for five days). The use of cytarabine as an antiviral agent has been restricted by the toxic effects produced with these regimens. We have treated ten patients with herpesvirus infections of wide range of severity using cytarabine infusions ranging from 10 to 100 mg/sq m /day for 1 1/2 to 7 days. In each case, the viral infection responded favorably soon after cytarabine therapy was started, even when low doses were given for short periods. The low-dose short-period infusions produced few toxic effects. Thus, cytarabine may be more useful as an antiviral agent than has previously been realized. Controlled studies are required to confirm this clinical impression.

The diagnoses most frequently to be considered when a newborn infant is found to have heart failure and cyanosis include congenital lesions of the heart shunting unoxygenated blood to the systemic circuit. Less frequently seen are primarily acyanotic lesions that cause cyanosis by virtue of the left heart failure they engender. 1 The recent literature contains several case reports of infants whose failure was due to large intracranial arteriovenous fistulae, but these were acyanotic until severe left heart failure developed. 2-12 We have recently observed a newborn boy with heart failure caused by an intracranial arteriovenous fistula, but who had cyanosis when he was in only moderate failure. Investigations revealed methemalbumin discoloring his plasma, and bilateral subdural hematomas. As the chocolate-colored fluid was removed from the subdural spaces, both his cyanosis and the plasma pigment cleared, without a significant change in his cardiac status. Report of Case A Caucasian boy