Autism: Will vitamin D supplementation during pregnancy and early childhood reduce the recurrence rate of autism in newborn siblings?

BACKGROUND: Vitamin D deficiency is widespread in the world including the vulnerable group of pregnant women. Vitamin D deficiency during pregnancy is hypothesized to contribute to the cause of autism. Further, it is hypothesized that vitamin D supplementation during pregnancy and early childhood will reduce the recurrence rate of autism in newborn siblings. METHODS: To investigate the hypothesis an open label prospective study was performed prescribing vitamin D during pregnancy to mothers of children with autism at a dose of 5000IU/day. The newborn siblings were at high risk for the recurrence of autism. The newborn infants were also prescribed vitamin D, 1000IU/day to their third birthday. The newborn siblings were followed for three years and during that time, were assessed for autism on two separate occasions: at 18months and 36months of age. The results were compared to the reported recurrence rates in siblings of autistic children in the literature. RESULTS: The final outcome was 1 out of 19 (5%) developed autism in contrast to the recurrence rate of approximately 20% in the literature. We did not have a control group, nor was there blinding. CONCLUSIONS: The results are promising, however, this is a preliminary study with very small numbers and was uncontrolled. Further study with larger numbers is indicated. The ethics of prescribing a low dosage of vitamin D such as 400IU D3/day to a control group of mothers in comparison to a large dose such as 5000IU D3/day are problematic in our opinion.

Translation inhibitors induce cell death by multiple mechanisms and Mcl-1 reduction is only a minor contributor.

There is significant interest in treating cancers by blocking protein synthesis, to which hematological malignancies seem particularly sensitive. The translation elongation inhibitor homoharringtonine (Omacetaxine mepesuccinate) is undergoing clinical trials for chronic myeloid leukemia, whereas the translation initiation inhibitor silvestrol has shown promise in mouse models of cancer. Precisely how these compounds induce cell death is unclear, but reduction in Mcl-1, a labile pro-survival Bcl-2 family member, has been proposed to constitute the critical event. Moreover, the contribution of translation inhibitors to neutropenia and lymphopenia has not been precisely defined. Herein, we demonstrate that primary B cells and neutrophils are highly sensitive to translation inhibitors, which trigger the Bax/Bak-mediated apoptotic pathway. However, contrary to expectations, reduction of Mcl-1 did not significantly enhance cytotoxicity of these compounds, suggesting that it does not have a principal role and cautions that strong correlations do not always signify causality. On the other hand, the killing of T lymphocytes was less dependent on Bax and Bak, indicating that translation inhibitors can also induce cell death via alternative mechanisms. Indeed, loss of clonogenic survival proved to be independent of the Bax/Bak-mediated apoptosis altogether. Our findings warn of potential toxicity as these translation inhibitors are cytotoxic to many differentiated non-cycling cells.

Field safety and efficacy of protamine zinc recombinant human insulin for treatment of diabetes mellitus in cats.

BACKGROUND: This study describes the efficacy of a new protamine zinc recombinant human insulin (PZIR) preparation for treating diabetic cats. OBJECTIVE: To evaluate effects of PZIR on control of glycemia in cats with newly diagnosed or poorly controlled diabetes mellitus. ANIMALS: One hundred and thirty-three diabetic cats 120 newly diagnosed and 13 previously treated. METHODS: Prospective, uncontrolled clinical trial. Cats were treated with PZIR twice daily for 45 days. Control of glycemia was assessed on days 7, 14, 30, and 45 by evaluation of change in water consumption, frequency of urination, appetite, and body weight, serum fructosamine concentration, and blood glucose concentrations determined 1, 3, 5, 7, and 9 hours after administration of PZIR. Adjustments in dosage of PZIR were made as needed to control glycemia. RESULTS: PZIR administration resulted in a significant decrease in 9-hour mean blood glucose (199+/-114 versus 417+/-83 mg/dL, X+/-SD, P<.001) and serum fructosamine (375+/-117 versus 505+/-96 micromol/L, P<.001) concentration and a significant increase in mean body weight (5.9+/-1.4 versus 5.4+/-1.5 kg, P=.017) in 133 diabetic cats at day 45 compared with day 0, respectively. By day 45, polyuria and polydipsia had improved in 79% (105 of 133), 89% (118 of 133) had a good body condition, and 9-hour mean blood glucose concentration, serum fructosamine concentration, or both had improved in 84% (112 of 133) of the cats compared with day 0. Hypoglycemia (<80 mg/dL) was identified in 151 of 678, 9-hour serial blood glucose determinations and in 85 of 133 diabetic cats. Hypoglycemia causing clinical signs was confirmed in 2 diabetic cats. CONCLUSIONS AND CLINICAL RELEVANCE: PZIR is effective for controlling glycemia in diabetic cats and can be used as an initial treatment or as an alternative treatment in diabetic cats that do not respond to treatment with other insulin preparations.

Tertiary trisomy due to a reciprocal translocation of chromosomes 5 and 21 in a four-generation family.

Tertiary trisomy, or double trisomy, is a rare occurrence. We present two individuals with a previously unreported tertiary trisomy for chromosomes 5p and 21q in an eight-generation pedigree. Their phenotypes are compared with other partial trisomies of either 5p or 21q from the literature. The propositus was diagnosed with trisomy 21 at 2 years of age after a karyotype study for short stature and developmental delay. His phenotype was described as atypical for Down syndrome. He presented at 9 years of age because of pervasive behavioral problems and obesity. He was brachycephalic with a flattened nasal bridge, but he lacked other characteristics of trisomy 21. Because of lack of phenotypic evidence of Down syndrome, a repeat karyotype was obtained and showed 47,XY, +der(21)t(5;21)(p15.1; q22.1), incorporating partial trisomies of both chromosomes 5 and 21. Mother had a balanced translocation, 46, XX,t(5;21)(p15.1; q22.1); 8 other relatives were examined. The translocation originated from the maternal great-grandmother, but only the propositus and his mentally retarded aunt had a similar phenotye and the derivative chromosome. Fluorescence in situ hybridization showed absence of band 21q22.2 in the derivative chromosome of the propositus and his aunt, indicating that neither had trisomy for the Down syndrome critical region. These cases represent a unique double partial trisomy of chromosome arms 5p and 21q that occurred because of 3:1 malsegregation of a reciprocal translocation. These cases further demonstrate that phenotypic discordance with cytogenetic results dictate further investigation using advanced cytogenetic hybridization.

Omeprazole or ranitidine bismuth citrate triple therapy to treat Helicobacter pylori infection: a randomized, controlled trial in Vietnamese patients with duodenal ulcer.

AIM: To evaluate the effectiveness of triple therapy containing either omeprazole or ranitidine bismuth citrate (RBC) to treat H. pylori infection in Vietnamese duodenal ulcer patients. METHODS: Patients infected with H. pylori were randomized to receive either omeprazole (20 mg b.d.), clarithromycin (500 mg b.d.) and amoxycillin (1 g b.d.) for 10 days (OAC), or RBC (400 mg b.d.), clarithromycin (500 mg b.d.) and amoxycillin (1 g b.d.) for 10 days (RAC). H. pylori eradication and ulcer healing was established by a follow-up oesophagogastroduodenoscopy (EGD) at least 4 weeks after therapy. Side-effects and compliance were assessed. RESULTS: One hundred and four out of 108 (96%) patients with a duodenal ulcer were infected with H. pylori. Eighty per cent of infected patients had detectable CagA IgG antibodies. Fifty-seven patients received OAC and 47 received RAC. OAC eradicated H. pylori in 91 and 86% of patients by per protocol (PP) and intention-to-treat (ITT) analysis, respectively. PP and ITT eradication rates for RAC were 96 and 91%. Ulcer healing at the follow-up EGD was 89% with OAC and 100% with RAC. Side-effects were minor. No patient failed to complete the protocol due to side-effects. CONCLUSION: Triple therapy with either omeprazole or RBC is highly effective in eradicating H. pylori and healing duodenal ulcer in Vietnamese patients.

Prostaglandins in liver disease and liver transplantation.

This brief review summarizes the physiology and pharmacology of eicosanoids and describes how they have been tested for possible application in liver disease and transplantation. The objective is to trace the stepwise application from the laboratory to the bedside. Although many questions remain to be answered, the observations summarized in this article have opened up new and potentially rewarding prospects in application to liver disease.

A cost analysis of alprostadil in liver transplantation.

Alprostadil (prostaglandin E1) administration to liver transplant recipients has been shown to result in a significant reduction in the duration of hospital admission for transplantation, and in the need for re-operations (other than re-transplants) and renal support. To study the economic impact of this finding, we examined data from a controlled trial for all single-transplant surviving patients (42 alprostadil, 49 controls) for whom complete billing records were available for transplant days -2 to +150. All costs were measured in 1992 US dollars. Patients given alprostadil had lower total charges [mean +/- standard deviation (SD) $US175 297 +/- $US70 652] than patients given placebo (mean +/- SD $US225 672 +/- $US187 208) [p = 0.043]. The data suggest that the use of alprostadil may have a significant favourable impact on the cost of liver transplantation.

Update of the Adult and Pediatric Liver Transplant Program at the University of Michigan.

Significant technical innovations and improvements in immunosuppression have been introduced into our liver transplant program since its inception in 1985. The indications for transplantation have been extended to younger and older patients, and simultaneously more patients with comorbidities have been accepted for transplant. The net impact of these changes has been a continuing trend toward improved survival. Overall, patients with hepatitis B or malignancy have had poor survival rates. The introduction of prophylactic anti-hepatitis B immunoglobulin and lamivudine, and better selection of patients with malignancy may improve results for these patients in the future. As in other programs, our most vexing problem is the continuing scarcity of donor organs which has led to an ever-expanding waiting list, more deaths while awaiting transplant, and more suffering before transplantation. The introduction of living donor hepatic transplantation will be of some help in alleviating this shortage. We are confident that the evolution of our program into a joint multidisciplinary structure will provide more efficient, convenient and cost-effective care to our patients.

A double-blind, randomized, placebo-controlled trial of prostaglandin E1 in liver transplantation.

A double-blind placebo-controlled trial of intravenous prostaglandin PGE1 (40 micrograms/h) was conducted in adult orthotopic liver transplant recipients. Infusion was started intraoperatively and continued for up to 21 days. Patients were followed up for 180 days postoperatively. Among 172 patients eligible for treatment in the study, 160 could be evaluated (78 PGE1; 82 placebo). Patient and graft survival were similar (PGE1: 16 deaths, 9 retransplantations [7 survivors]; controls: 15 deaths, 6 retransplantations [3 survivors]). In patients with surviving grafts, however, PGE1 administration resulted in a 23% shorter mean duration of hospitalization following transplantation (PGE1: 24.4 days; controls: 31.8 days; P = .02) and a 40% shorter length of time postoperatively in the intensive care unit (PGE1: 8.2 days; controls 13.7 days; P = .05). Reduced needs for renal support (P = .03) or surgical intervention other than retransplantation (P = .02) were also noted with PGE1 use. Further, PGE1 administration resulted in a trend toward improved survival rates in patients with mild renal impairment (preoperative serum creatinine 1.5 mg percent or greater; P = .08). Neither the incidence of acute cellular rejection nor of primary nonfunction was significantly different in the two groups. Phlebitis was the only complication that was more common during PGE1 administration, (PGE1: 9; controls: 4). These results suggest that PGE1 use in hepatic allograft recipients reduces morbidity and may result in sizable cost reductions.

Acute cellular rejection after liver transplantation: variability, morbidity, and mortality.

Acute cellular rejection of the allograft is a potentially serious complication after liver transplantation, yet its true incidence is unknown. We therefore investigated the frequency of acute cellular rejection reported by transplant centers and its impact on morbidity and mortality. Morbidity was defined as duration of hospitalization. Of 200 articles screened, 18 were selected for inclusion in the study database, in which there was a total of 1,437 patients who received transplants. All contained more than 20 patients and invariably used histopathology for diagnosis of acute cellular rejection. These reports included all transplant patients within a fixed period and sufficient data to determine the incidence of acute cellular rejection. Morbidity data were obtained from our previous series. The mean incidence of acute cellular rejection in all centers was 49.8% (range between centers, 24% to 80%). Two immunosuppressive cohorts were identified: high-dose cyclosporine induction (> or = 5 mg/kg/d) and low-dose cyclosporine induction (< or = 4 mg/kg/d). Acute cellular rejection was reported in 27.0% of the high-dose group and 63.6% of the low-dose group, P = .0001. Strict adherence to Snover's histological criteria for acute cellular rejection did not alter the reported mean incidence. Frequency of acute cellular rejection was 45.2% (range between centers, 24% to 80%) in 8 studies that used Snover's criteria, and 51.6% (range between centers, 37% to 80%) in 10 studies that did not. There was no correlation between mortality and incidence of acute cellular rejection in the 9 studies that reported survival (R2 = .105). Morbidity data showed that the average length of initial hospitalization after transplantation for patients with acute cellular rejection was 52.4 +/- 8.3 (range, 14 to 124) days, in contrast to 28.3 +/- 2.3 (range, 9 to 87) days for patients with no rejection. P = .0008. The total number of hospital days in the first 6 months for patients with acute cellular rejection was 55.6 +/- 8.6 (range, 14 to 124) days and with no rejection, was 37.7 +/- 3.1 (range, 9 to 99) days. P = .0232. The incidence of acute cellular rejection varies widely among transplant centers, regardless of the use of Snover's criteria. Acute cellular rejection appeared to be less frequent in programs using high-dose cyclosporine induction regimens. The presence of acute cellular rejection seemed to have no correlation with mortality but significantly increased morbidity and therefore the cost of transplantation.

Nalmefene enhances LH secretion in a proportion of oligo-amenorrheic athletes.

The influence upon LH secretion of doses of nalmefene, an orally effective congener of naloxone, and a placebo was compared in nine oligo-amenorrheic athletes with that in five regularly menstruating non-athletic women as a test for periodic elevations in hypothalamic opioid tone. After a 360-min control period, LH levels were followed for an additional 360 min following ingestion of the medications in random order approximately six weeks apart, 10-min blood sampling being employed throughout. The mean amplitude post-nalmefene in the athletes was significantly greater than pre (p < 0.05), although there were no differences in the frequency of LH pulses after placebo or nalmefene ingestion. Subjects were labelled as "responders" if their peak AUC after treatment exceeded their pretreatment AUC for LH by more than 1.96 SD (p < 0.05). There were no placebo responders, but 5/9 of the athletes and 1/5 of the menstruating controls were classified as nalmefene responders (p < 0.05). In addition, a variable proportion of the athletes (but none of the controls) experienced symptoms suggestive of narcotic withdrawal 1-4 h after ingesting nalmefene and again 12-18 h later. It appears that demonstrable increases in opioid tone occur at least transiently in a proportion of oligo-amenorrheic athletes.

Preoperative risk factor assessment in liver transplantation.

BACKGROUND: Despite the increasing success of liver transplantation, there is lack of objective data defining appropriate candidate suitability. This study was undertaken to determine preoperative risk factors that independently or in combination affected outcome after orthotopic liver transplantation. METHODS: We reviewed data on 229 consecutive adult liver transplant recipients. Thirty-one preoperative risk factors recorded at the time of listing and immediately before transplantation were analyzed. Outcome variables included hospital mortality rates, bacterial or fungal sepsis, and the need for renal support. RESULTS: The overall hospital mortality rate was 15.7%. Patients who were in the intensive care unit immediately before transplantation had the highest hospital mortality rate (32.6%; p = 0.006), incidence of bacterial sepsis (51%; p = 0.001), fungal infection rate (27.6%; p = 0.001), and need for renal support (38.7%; p = 0.001). Preoperative renal dysfunction was significantly associated with sepsis and was reflected in higher hospital mortality rates (29.5%; p = 0.011). Child-Pugh class C was associated with higher mortality rates (23.9%; p = 0.017), an increased incidence of bacterial (37.2%; p = 0.020) and fungal infection (20.3%; p = 0.049), and a 30.4% requirement for postoperative renal support (p = 0.004). CONCLUSIONS: These results emphasize the need for earlier referral and transplantation in patients with advanced liver disease. Further studies are needed to refine identified risk profiles and devise strategies to decrease morbidity and mortality rates.

Biochemical and histopathological correlation in liver transplant: the first 180 days.

It is not known whether the histopathology of the liver allograft can be predicted from biochemical measurements in serum with the same confidence as in the native liver. To answer this question we compared the histopathological diagnoses in 170 biopsy specimens from 70 adult transplant recipients obtained during the first 180 days, with the concentrations of the serum bilirubin and the activities of AST, ALT and alkaline phosphatase measured at the same time. The most frequent diagnosis was cholestasis (n = 45), which was mild, moderate or severe and which may have been complicated by rejection (n = 28) or ischemia (n = 14). Hepatitis (n = 14), ischemia with rejection (n = 6) and spotty focal necrosis (n = 6) were diagnosed less frequently. Fifteen biopsy specimens were reported as histopathologically normal. In general, biochemical measurements discriminated poorly between different histopathological diagnoses. The histopathologically normal liver often showed an abnormal pattern of enzymes and an increase in the serum bilirubin level. As a result histopathologically normal biopsy specimens were indistinguishable biochemically from those with hepatitis. When two pathological conditions were found to coexist (e.g., cholestasis with either rejection or ischemic necrosis, or ischemic necrosis with rejection), the effect on the serum biochemistry was usually not additive and in some instances returned the biochemical abnormalities toward normal. With the exception of the serum bilirubin level, which increased with the severity of uncomplicated cholestasis, we could not identify a specific pattern of biochemical changes corresponding to a given histopathological diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Selection for and outcome of liver transplantation in alcoholic liver disease.

It has been proposed that evaluation of alcoholic patients for liver transplantation should comprise a multidisciplinary program including medical, surgical, and psychiatric assessment. This article presents the outcome in 99 alcoholic persons evaluated from 1985 through 1989. Alcoholism was defined as alcohol dependence or abuse according to the DSM-III-R. Forty-five patients (43%) were considered suitable candidates and underwent transplantation. Actuarial survival in this group was 78% and 73% at 12 and 24 months, respectively, and did not differ from that observed in nonalcoholic recipients. Return to alcohol use after transplantation has been documented in 5 persons, 2 of whom have had episodes of uncontrolled drinking. Of 54 patients not selected for transplantation, 17 were considered too well and suitable for alternative therapy. Actuarial survival was 93% at 12 and 18 months but declined to 59% at 24 months. Nineteen patients were medically unsuitable and had very poor survival; survival was 35% at 3 months and 0% at 12 months. Seventeen patients were not selected on psychiatric grounds. Actuarial survival in this group (65% at 12 months, 43% at 18 months) was significantly less than that in alcoholics with transplants (P less than 0.05). There were no differences in age, sex ratio, degree of hepatic dysfunction, or duration of abstinence between alcoholics with transplants and those considered psychiatrically unsuitable. It was concluded that liver transplantation is successful in selected patients with alcoholic cirrhosis, that patients who are not selected because they are "too well" need continuing surveillance as a significant decline in survival can occur 18-24 months after initial evaluation and, finally, that patients not selected on psychiatric grounds have a significantly worse survival rate than those with transplants.