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Biomedical subjects

M J Solomon

Publications and source records attributed to M J Solomon.

At least 55 records · Page 3Linked to original sources
PubMed1998

Successful overlapping anal sphincter repair: relationship to patient age, neuropathy, and colostomy formation.

BACKGROUND: Fecal incontinence from single anal sphincter defects are surgically remedial and commonly the result of obstetric injuries. Overlapping anal sphincter repair has previously been associated in small series with good results in 69 to 97 percent of patients. OBJECTIVES: The aims of this study were to assess the results of overlapping anal sphincter repair in one institution and to assess the effects of age, presence of a neuropathy, and addition of a temporary colostomy on the success of surgery. METHODS: A study of 57 overlapping anal sphincter repairs in 56 (54 females) patients at the Royal Prince Alfred Hospital during a six-year period was performed. All patients were investigated preoperatively with endoanal ultrasound and concentric needle electromyography. Patients have been assessed prospectively since 1994 with a questionnaire, including a four-point Likert scale of continence level, the St. Mark's incontinence scoring system (range, 0-13), the Pescatori incontinence scoring system (range, 0-6), and patient assessment of success or failure of the overlapping anal sphincter repair. A colostomy was selectively formed in conjunction with an overlapping anal sphincter repair in 21 patients (8 preoperatively, 13 simultaneously), and 18 patients had a concomitant neuropathy (3 unilateral, 15 bilateral). RESULTS: After a median follow-up of 18 months, median continence scores overall had improved from St. Mark's incontinence scoring 13 to 3 (P < 0.0001) and Pescatori incontinence scoring 6 to 2 (P < 0.0001). Forty-nine of 57 (86 percent) repairs have been successful, and 8 are considered to be failures. Twenty-one of 27 (78 percent) repairs in patients younger than 40 years of age were successful, as were 28 of 30 (93 percent) repairs in patients older than 40 years of age (P = 0.10). Four of 18 (22 percent) repairs associated with a neuropathy failed compared with 4 of 39 (10 percent) without a neuropathy (P = 0.21). Improved or normal continence was achieved in 17 of 21 (81 percent) patients with a stoma and overlapping anal sphincter repair and in 32 of 36 (89 percent) patients with an overlapping anal sphincter repair alone (P = 0.32). The presence of a stoma did not improve the rate of wound healing by primary intention (62 percent for stoma vs. 64 percent for overlapping anal sphincter repair alone; P = 0.55). CONCLUSIONS: Single anal sphincter defects can be successfully treated with an overlapping anal sphincter repair. There is no improvement in primary healing with selective stoma formation. Age of the patient and presence of a neuropathy should not detract from proceeding with overlapping anal sphincter repair when singular anal sphincter defects are detected on endoanal ultrasound in muscle that is still active.

Adolescent↗
PubMed1998

Defunctioning of the anorectum: historical controlled study of laparoscopic vs. open procedures.

BACKGROUND: Creating a defunctioning stoma for anorectal disease in patients in whom no resection or anastomosis is required appears eminently suited for laparoscopic techniques, with the intended advantages of early recovery, reduced pain, and avoidance of a laparotomy. OBJECTIVES: The study contained herein was undertaken to determine the feasibility of laparoscopic defunctioning stoma formation using a three-port technique (including one at the stoma site) and to compare initial results with a historical control group. METHODS: Duration of operation (anesthetic plus surgery), the time to tolerance of a liquid and then a solid diet, time to passage of flatus and feces, patient morphine requirements in the first 48 hours, and day of discharge were documented. RESULTS: Nineteen laparoscopic stomas were attempted (3 converted to open) and 23 open stomas were formed in the control group. The laparoscopic stoma group had lower morphine requirements (mean, 47.7 vs. 89.9 mg; P < 0.01), an earlier tolerance of both liquid (mean, 2.1 vs. 3.7 days; P < 0.01) and solid diets (mean, 3.6 vs. 5.5 days; P < 0.001), and an earlier time to passage of both flatus (mean, 2.2 vs. 3.6 days; P < 0.001) and feces (mean, 3.7 vs. 5.6 days; P < 0.001). Operating time was longer for the laparoscopic group (mean, 176 vs. 104 minutes; P < 0.001), whereas median time to discharge from hospital was shorter (median, 8 vs. 11 days; P = 0.014). Postoperative 30-day morbidity occurred in 1 of 19 laparoscopic group patients and 4 of 23 open group patients. CONCLUSIONS: In this select group of patients requiring defunctioning stoma only, laparoscopic surgery is feasible and safe and may have advantages over open procedures of less pain, earlier tolerance of diet, earlier return of bowel function, and a shorter median length of stay.

Adult↗
PubMed1998

Cancer and inflammatory bowel disease: bias, epidemiology, surveillance, and treatment.

Individuals with chronic ulcerative colitis are at increased risk of developing colorectal carcinoma, particularly if there is long-standing disease or extensive colitis. It is generally accepted that the risk of colorectal cancer does not begin until 8 to 10 years after the time of diagnosis of ulcerative colitis. Thereafter it increases by approximately 0.5% to 1.0% per year. In patients with Crohn's disease, the risk of malignancy is smaller and less well defined. The most significant predictor of the risk of malignancy in patients with inflammatory bowel disease is the presence of dysplasia in colonic biopsies. There is considerable controversy in the literature regarding the efficacy of colonoscopic surveillance programs and the role of prophylactic surgery to prevent colorectal cancer. Surveillance certainly fails to detect carcinoma in some patients who are having regular colonoscopy. Concerns have also been raised as to the cost-benefit of colonoscopic surveillance in patients with colitis. Randomized controlled trials of surveillance programs are highly unlikely in view of the low prevalence of IBD in the population, the long period of observation required, and the probability of contamination of surveillance programs by colonoscopy for assessment of disease activity. Despite the lack of clear guidelines, surveillance colonoscopy and biopsy continues to be widely practiced. Research is proceeding to identify genetic and biochemical markers that may prove clinically useful for predicting cancer risk. At present, however, surveillance programs are likely to continue according to institutional practice. It is important for those participating in such programs to be aware of the limitations of colonoscopy and biopsy as a means of reducing the risk of cancer in inflammatory bowel disease.

Bias↗
PubMed1998

Human and yeast cdk-activating kinases (CAKs) display distinct substrate specificities.

Cell cycle progression is controlled by the sequential functions of cyclin-dependent kinases (cdks). Cdk activation requires phosphorylation of a key residue (on sites equivalent to Thr-160 in human cdk2) carried out by the cdk-activating kinase (CAK). Human CAK has been identified as a p40(MO15)/cyclin H/MAT1 complex that also functions as part of transcription factor IIH (TFIIH) where it phosphorylates multiple transcriptional components including the C-terminal domain (CTD) of the large subunit of RNA polymerase II. In contrast, CAK from budding yeast consists of a single polypeptide (Cak1p), is not a component of TFIIH, and lacks CTD kinase activity. Here we report that Cak1p and p40(MO15) have strikingly different substrate specificities. Cak1p preferentially phosphorylated monomeric cdks, whereas p40(MO15) preferentially phosphorylated cdk/cyclin complexes. Furthermore, p40(MO15) only phosphorylated cdk6 bound to cyclin D3, whereas Cak1p recognized monomeric cdk6 and cdk6 bound to cyclin D1, D2, or D3. We also found that cdk inhibitors, including p21(CIP1), p27(KIP1), p57(KIP2), p16(INK4a), and p18(INK4c), could block phosphorylation by p40(MO15) but not phosphorylation by Cak1p. Our results demonstrate that although both Cak1p and p40(MO15) activate cdks by phosphorylating the same residue, the structural mechanisms underlying the enzyme-substrate recognition differ greatly. Structural and physiological implications of these findings will be discussed.

CDC2-CDC28 Kinases↗
PubMed1998

Intraocular penetration of gentamicin after once-daily aminoglycoside dosing.

BACKGROUND: Intraocular concentrations-particularly intravitreal concentrations-after systemic administration of gentamicin are poor. Once-daily aminoglycoside dosing of intravenous gentamicin achieves peak serum levels up to five times higher than conventional dosing. Whether these increased serum levels of gentamicin improve the aqueous or vitreous concentrations in humans has not been determined. The authors sought to determine if the intraocular penetration of gentamicin would be improved using this method. METHODS: Patients undergoing vitrectomy procedures were administered intravenous gentamicin in a dose of 7 mg/kg approximately 1 hour before surgery. An adjustment in dosing was made for anyone more than 20% over his or her ideal body weight. Aqueous, vitreous, and serum samples were collected before any intraocular surgical manipulation. The samples were analyzed by fluorescence polarization immunoassay (TDx system). RESULTS: The average single gentamicin dose was 498 mg (range, 360-700 mg). The aqueous, vitreous, and serum levels averaged 1.14 microg/mL, 0.41 microg/mL, and 22.07 microg/mL, respectively. No correlation between serum level concentrations and time of administration was found for the aqueous and vitreous levels in this study. CONCLUSION: Although the average peak serum level of gentamicin was five times higher than previously reported, the vitreous levels averaged only 1.5 times higher. The blood-retinal barrier is difficult to penetrate even when higher serum levels are achieved. Due to its poor ocular penetration, gentamicin may not be among the best drugs for prophylaxis of penetrating eye injuries, surgical prophylaxis, or treatment of endophthalmitis.

Anti-Bacterial Agents↗
PubMed1998

Cyclin-stimulated binding of Cks proteins to cyclin-dependent kinases.

Although Cks proteins were the first identified binding partners of cyclin-dependent protein kinases (cdks), their cell cycle functions have remained unclear. To help elucidate the function of Cks proteins, we examined whether their binding to p34(cdc2) (the mitotic cdk) varies during the cell cycle in Xenopus egg extracts. We observed that binding of human CksHs2 to p34(cdc2) was stimulated by cyclin B. This stimulation was dependent on the activating phosphorylation of p34(cdc2) on Thr-161, which follows cyclin binding and is mediated by the cdk-activating kinase. Neither the inhibitory phosphorylations of p34(cdc2) nor the catalytic activity of p34(cdc2) was required for this stimulation. Stimulated binding of CksHs2 to another cdk, p33(cdk2), required both cyclin A and activating phosphorylation. Our findings support recent models that suggest that Cks proteins target active forms of p34(cdc2) to substrates.

Animals↗
PubMed1997

Incidence of free colorectal cancer cells on the peritoneal surface.

BACKGROUND: The etiology and significance of port site recurrence occurring after laparoscopic-assisted resection for colorectal cancers will not be determined until controlled clinical trials determine if it is a predictor of outcome. Indirect evidence in support of transcoelomic spread of viable cancer cells to port sites during resection can be postulated by the presence of free cells on the fresh surface of colorectal specimens during primary resection. PURPOSE: The study contained herein was undertaken to determine the incidence of free surface colorectal cancer cells by cytology during elective open resection and to correlate their presence with clinicopathologic variables. METHODS: Fresh clamped and ligated consecutive colorectal cancer specimens were assessed in the operating room during primary resection for the presence of free colorectal cancer cells during an 18 month period at one institution. Clinicopathologic variables were assessed prospectively and blinded to cytology results. Interobserver reliability of cytologists was excellent (unweighted kappa, 0.93). RESULTS: Overall, 15 of 103 (14.6 percent) colorectal cancers had positive cytology for cancer cells on the peritoneal or perirectal surface of the bowel. T3 and T4 tumors, the size or site of the tumor, lymph node status, mucinous characteristic, degree of differentiation, and the presence of vascular or neural invasion did not reach statistical significance as predictors of positive cytology in this study sample. The operative procedure performed was a statistically significant predictor of positive cytology. More than 50 percent of lymph nodes involved (28 percent), poorly differentiated tumors (28 percent), and the presence of liver metastases (22 percent) demonstrated a higher incidence of positive cytology, but this did not reach significant levels because of the limited power of the study sample for subgroup analysis. DISCUSSION: The presence of free surface colorectal cancer cells gives only indirect support to the transcoelomic route to port site recurrence. The significance and true incidence will only be determined by prospective database analysis and randomized, controlled trials.

Adenocarcinoma↗
PubMed1997

Construction and characterization of retroviral vectors for interleukin-2 gene therapy.

Several investigators have employed interleukin-2 (IL-2) gene transfer to enhance the immunogenicity of tumor cell vaccines. We describe in this report the construction and characterization of retroviral vectors for IL-2 gene therapy. Human IL-2 cDNA with a chimeric rat preproinsulin/IL-2 DNA leader sequence was subcloned into the pLXSN (long terminal repeat promoter) and pLNCX (cytomegalovirus [CMV] promoter) vectors to generate the plasmids pLXSN-iIL2 and pLNCX-iIL2, respectively. Human IL-2 cDNA with a chimeric human tissue factor/IL-2 DNA leader sequence was utilized to construct the vector pLXSN-tIL2. The levels of IL-2 secreted by transduced tumor cells and fibroblasts were evaluated by enzyme-linked immunosorbent assay (ELISA) of culture supernatants and compared with those of normal peripheral blood mononuclear cells (PBMC) activated in vitro with calcium ionophore and phorbol 12-myristate 13-acetate. The highest levels of IL-2 secreted by transduced tumor cells (760 units/10(6) cells/24 h), adult fibroblasts (625 units/10(6) cells/24 h), and embryonic fibroblasts (3,975 units/10(6) cells/24 h) were 150- to 1,000-fold higher than than secreted by the activated PBMC (4 units/10(6) cells/24 h). Similar levels of IL-2 were expressed by human fibroblasts transduced with pLXSN vectors employing the preproinsulin (pLXSN-iIL2) or tissue factor (pLXSN-tIL2) leader sequences (range in IL-2 units/10(6) cells/24 h pLXSN-iIL2 = 375-625 vs. pLXSN-tIL2 = 90-440). Because IL-2-transduced cells for clinical applications are generally irradiated to prevent cellular proliferation, we evaluated the effects of radiation on IL-2 production. Radiation doses between 1,500 and 10,000 cGy resulted in gradual decreases in IL-2 secretion by transduced cells. The range of the decrease in IL-2 secretion was 7-11% by day 7, 0-29% by day 14, and 25-50% by day 35. For clinical applications, stable production of the vector in high concentrations is an important consideration. The retroviral vector pLXSN-tIL2 produced the highest viral titer and was chosen for further characterization. Southern blot analysis of SacI-digested genomic DNA from the LXSN-tIL2 producer cell line and SacI-digested pLXSN-tIL2 plasmid DNA revealed the expected 3.2-kbp fragment, suggesting the absence of transgene rearrangement and the suitability of this vector as a candidate for clinical applications.

3T3 Cells↗
PubMed1997

Ofloxacin penetration into the eye after intravenous and topical administration.

PURPOSE: To determine the aqueous and vitreous fluid penetration of ofloxacin after a combined topical and single intravenous dose protocol before vitrectomy surgery. MATERIALS AND METHODS: Before undergoing vitrectomy surgery, patients were given two drops of ofloxacin 0.3% topically and a single intravenous dose of ofloxacin 400 mg. Aqueous (mean, 43 minutes) and vitreous (mean, 53 minutes) fluid samples were collected at the start of the surgical procedure. The samples were analyzed for ofloxacin penetration. RESULTS: The mean aqueous fluid concentration was 1.083 micrograms/mL +/- 0.406. The mean +/- SD vitreous fluid concentration in nondiabetic patients with intact vitreous was 0.352 microgram/mL +/- 0.301. Vitreous levels obtained more than 50 minutes after administration (0.414 microgram/mL +/- 0.336) were generally higher than those obtained after less than 50 minutes (P = 0.12). Eyes with prior vitrectomies achieved better ofloxacin penetration (0.984 microgram/mL +/- 0.680) than did nonvitrectomized eyes. CONCLUSION: Ofloxacin achieved measurable aqueous fluid penetration after topical and intravenous administration. Aqueous levels were above the minimum inhibitory concentration for most ocular pathogens. Vitreous levels were adequate in vitrectomized eyes to achieve inhibitory concentrations against many common ocular pathogens. Combined preoperative topical and a single dose of intravenous ofloxacin may provide inhibitory aqueous and vitreous antibiotic levels in vitrectomized eyes in cases where intravitreal antibiotics are not considered and oral administration is not practical.

Administration, Topical↗
PubMed1996

A predictive scale for evaluating cyclin-dependent kinase substrates. A comparison of p34cdc2 and p33cdk2.

Protein phosphorylation by members of the Cdk (cyclin-dependent kinase) family of protein kinases is necessary for progression through the cell cycle. However, the primary sequence determinants of Cdk substrate specificity have yet to be examined quantitatively. We have used a panel of glutathione S-transferase peptide fusions to investigate the fine-structure specificity of p33(cdk2) and p34(cdc2). Our data indicate that the generally held consensus sequences for p34(cdc2) represent a significant oversimplification of its true specificity and that this specificity is conserved between species. p33(cdk2) and p34(cdc2) have similar but distinct substrate specificities that are affected modestly by the associated cyclin subunit. We derive specific values of phosphorylation efficiencies by these enzymes that can be used to estimate the phosphorylation potential of proposed Cdk substrates.

Amino Acid Sequence↗
PubMed1996

The Cdk-activating kinase (CAK) from budding yeast.

Activation of the cyclin-dependent kinases to promote cell cycle progression requires their association with cyclins as well as phosphorylation of a threonine (residue 161 in human p34cdc2). This phosphorylation is carried out by CAK, the Cdk-activating kinase. We have purified and cloned CAK from S. cerevisiae. Unlike CAKs from other organisms, Cak1p is active as a monomer, has full activity when expressed in E. coli, and is not a component of the basal transcription factor, TFIIH. A temperature-sensitive mutation in CAK1 confers a G2 delay accompanied by low Cdc28p protein kinase activity and shows genetic interactions with altered expression of the gene for the major mitotic cyclin, CLB2. Our data raise the intriguing possibility that p40MO15-cyclin H-MAT1, identified as the predominant CAK in vertebrate cell extracts, may not function as a physiological CAK.

Amino Acid Sequence↗
PubMed1996

Gracilis myocutaneous flap to reconstruct large perineal defects.

Large perineal defects can occur after surgery for recurrent malignancy particularly after adjuvant radiotherapy or in complex chronic perineal inflammatory conditions. Quality of life can be severely impaired by perineal wounds or chronic sinuses. Muscle and myocutaneous flaps can be used to close large defects, increase vascular supply to poorly healing wounds, and provide bulk for sitting. We report 5 cases where the gracilis flap was used to repair large perineal defects. The defects were created after wide perineal excision for recurrent tumours associated with radiation damaged skin (2 cases) and after excision of chronic sinuses complicating the perineal wounds after abdominoperineal excision of the anus for inflammatory bowel disease (3 cases).

Adult↗