Ileoanal reservoir for ulcerative colitis and familial polyposis

Although total proctocolectomy with permanent ileostomy is regarded as the definitive therapy for ulcerative colitis and familial polyposis, psychologic and physical complications with this operation have stimulated the development of the operation of total abdominal colectomy, mucosal proctectomy, ileal reservoir, and ileoanal anastomosis as an alternative surgical procedure. Since 1980, 104 of these operative procedures have been completed with no operative mortality; experience has been gained with both the J- and S-type reservoirs. Despite an appreciable number of postoperative complications, satisfactory function of the reservoir has been achieved in 86 of 91 patients followed up for at least three months after closure of the ileostomy. The remaining five patients have required reinstitution of fecal diversion. Functional results have not differed between two-limbed and three-limbed reservoirs. This operation must be considered a viable alternative in patients with ulcerative colitis and familial polyposis.     

Detection of the Glanzmann's thrombasthenia mutations in Arab and Iraqi-Jewish patients by polymerase chain reaction and restriction analysis of blood or urine samples.

Severe Glanzmann's thrombasthenia is relatively frequent in Iraqi-Jews and Arabs residing in Israel. We have recently described the mutations responsible for the disease in Iraqi-Jews--an 11 base pair deletion in exon 12 of the glycoprotein IIIa gene, and in Arabs--a 13 base pair deletion at the AG acceptor splice site of exon 4 on the glycoprotein IIb gene. In this communication we show that the Iraqi-Jewish mutation can be identified directly by polymerase chain reaction and gel electrophoresis. With specially designed oligonucleotide primers encompassing the mutation site, an 80 base pair segment amplified in healthy controls was clearly distinguished from the 69 base pair segment produced in patients. Patients from 11 unrelated Iraqi-Jewish families had the same mutation. The Arab mutation was identified by first amplifying a DNA segment consisting of 312 base pairs in controls and of 299 base pairs in patients, and then digestion by a restriction enzyme Stu-1, which recognizes a site that is absent in the mutant gene. In controls the 312 bp segment was digested into 235 and 77 bp fragments, while in patients there was no change in the size of the amplified 299 bp segment. The mutation was found in patients from 3 out of 5 unrelated Arab families. Both Iraqi-Jewish and Arab mutations were detectable in DNA extracted from blood and urine samples. The described simple methods of identifying the mutations should be useful for detection of the numerous potential carriers among the affected kindreds and for prenatal diagnosis using DNA extracted from chorionic villi samples.     

Self-administered heroin and cocaine combinations in the rat: additive reinforcing effects-supra-additive effects on nucleus accumbens extracellular dopamine.

The concurrent use of cocaine and opiate combinations (speedball) has increased since the 1970s and now represents a growing subset of intravenous drug abusers. An isobolographic analysis was applied to the ascending limb of the dose-effect curves for rat self-administration of cocaine, heroin, and their combination to determine the nature of the interaction. The addition of heroin to cocaine shifted the dose-effect curve for self-administration to the left, and the modulation in reinforcing efficacy of the combination of cocaine and heroin was found to be additive. A second experiment used microdialysis to determine the effects of this drug combination on nucleus accumbens (NAc) extracellular levels of dopamine ([DA](e)) in rats self-administering low doses of cocaine, heroin, or cocaine/heroin combinations. These doses of cocaine and cocaine/heroin combinations significantly increased NAc [DA](e), while heroin alone did not. The ratio of the % baseline of [DA](e) (or the dialysate concentrations of DA) to cocaine in the dialysate was higher during self-administration of cocaine/heroin combinations than with cocaine alone. These data indicate that although the interaction between cocaine and heroin in maintaining self-administration is additive, a potentiation of NAc dopaminergic neurotransmission is present, suggesting that NAc [DA](e) may not be a direct measure of reinforcing efficacy and/or it is not central to the mediation of the self-administration of this drug combination.     

mRNA stabilization by poly(A) binding protein is independent of poly(A) and requires translation

Translation and mRNA stability are enhanced by the presence of a poly(A) tail. In vivo, the tail interacts with a conserved polypeptide, poly(A) binding protein (Pab1p). To examine Pab1p function in vivo, we have tethered Pab1p to the 3′ UTR of reporter mRNAs by fusing it to MS2 coat protein and placing MS2 binding sites in the 3′ UTR of the reporter. This strategy allows us to uncouple Pab1p function from its RNA binding activity. We show that mRNAs that lack a poly(A) tail in vivo are stabilized by Pab1p, and that the portions of Pab1p required for stabilization are genetically distinct from those required for poly(A) binding. In addition, stabilization by Pab1p requires ongoing translation of the mRNA. We conclude that the primary, or sole, function of poly(A) with respect to mRNA stability is simply to bring Pab1p to the mRNA, and that mRNA stabilization is an intrinsic property of Pab1p. The approach we describe may be useful in identifying and assaying 3′ UTR regulatory proteins, as it uncouples analysis of function from RNA binding.     

Association between the DRD2 A1 allele and response to methadone and buprenorphine maintenance treatments.

The TaqI A polymorphism (A(1)) of the dopamine D(2) receptor gene (DRD2), although not a specific predictor of opioid dependence, has been strongly associated with high levels of prior heroin use and poor treatment outcomes among methadone maintenance patients. The aims of this study were to confirm these findings via a retrospective analysis of A(1) allele frequency in methadone (n = 46) and buprenorphine (n = 25) patients, and non-opioid-dependent controls (n = 95). Subjects were genotyped at the DRD2 TaqI A locus using PCR amplification followed by TaqI restriction enzyme digestion and gel electrophoresis. For methadone and buprenorphine subjects, heroin use (prior to treatment), treatment outcomes, and withdrawal occurrence were determined from comprehensive case notes. No significant differences in A(1) allele frequency (%) were observed between: methadone (19.6%), buprenorphine (18.0%), and control (17.9%) groups (P > 0.7); successful and poor treatment outcome groups, methadone: 20.0% and 19.2%, respectively (P = 1.0); buprenorphine: 18.4% and 20.0%, respectively (P = 1.0). Also, there were no significant relationships between TaqI A genotype and prior heroin use (P = 0.47). However, among the successful methadone subjects, significantly fewer A(1) allele carriers experienced withdrawal than non-A(1) carriers (P = 0.04). In conclusion, the DRD2 genotype effects did not affect opioid maintenance treatment outcomes. This suggests the need for a further prospective investigation into the role of the DRD2 A(1) allele in heroin use and response to maintenance pharmacotherapies for opioid dependence.     

Relationship between manometric anal waves and fecal incontinence

PURPOSE: The significance of manometric anal waves is uncertain, and their fate and diagnostic importance are unknown. It is conceivable that in neurogenic fecal incontinence (NFI) the frequency and amplitude of these waves may be altered into specific, recognizable patterns. Evaluation of this unexplored relationship between fecal incontinence and anal manometric waves has potential diagnostic use. METHODS: Anal motility was studied in 20 patients, each with NFI and traumatic fecal incontinence (TFI), and results were compared with findings in 20 control subjects to determine changes in frequency and amplitude of anal waves in fecal incontinence. RESULTS: Frequency of slow waves when present (NFI=9.5/minute; TFI=9.5/minute; control subjects=9.1/minute) was identical in the three groups (P>0.05). Amplitude of slow waves (NFI=mean, 4.3 mmHg; TFI=mean, 3.9 mmHg; control subjects =mean, 6.6 mmHg) was reduced in patients who were incontinent compared with control subjects but failed to reach statistical significance (P>0.05). Frequency of ultraslow waves when present (NFI=mean, 0.75/minute; TFI =mean, 0.6/minute; control subjects=mean, 1.2/minute) was not statistically different between the three groups (P>0.05). Amplitude of ultraslow waves (NFI=mean, 10.5 mmHg; TFI=mean, 23.4 mmHg; control subjects=mean, 29.6 mmHg) was significantly reduced in NFI vs.control subjects (P<0.01) and between TFI vs.control subjects (P<0.05). CONCLUSIONS: Manometric slow and ultraslow waves, when present, retain their frequency characteristics, irrespective of underlying disease. Amplitude of slow waves was not statistically different from control subjects, but the amplitude of ultraslow waves was significantly decreased in patients who were incontinent.