Biomedical subjects

G Marra

Publications and source records attributed to G Marra.

At least 73 records · Page 4Linked to original sources

PubMed1995

In vitro transcription/translation assay for the screening of hMLH1 and hMSH2 mutations in familial colon cancer.

BACKGROUND & AIMS: Hereditary nonpolyposis colorectal cancer (HNPCC) has been linked recently to a defect in repairing mismatched nucleotides in DNA. The aim of this study was to screen for germline mutations that result in prematurely truncated proteins in two of the mismatch repair genes identified at this time, hMLH1 and hMSH2, in a consecutive series of patients belonging to familial aggregations of colorectal cancer. METHODS: Nineteen individuals with colorectal cancer from 19 families were consecutively referred because of a strong positive family history of colorectal cancer. Premature truncation mutations in hMLH1 and hMSH2 were sought from lymphocyte RNA by using an in vitro transcription/translation (IVTT) assay. RESULTS: Protein truncating mutations in the hMLH1 or hMSH2 genes were found in 50% of families with HNPCC (6 of 12) but were not observed in any of the remaining familial aggregations that did not fulfill the standard criteria for HNPCC. In some of the IVTT-positive samples, the mutations were characterized by genomic sequencing. CONCLUSIONS: IVTT may be a practical method to accomplish primary screening of germline mutations in DNA mismatch pair genes in HNPCC; however, a broader approach is necessary to obtain a more complete picture of the mutational spectrum in HNPCC and other familial aggregations of colorectal cancer.

Base Sequence↗

PubMed1995

The effect of family size on estimates of the frequency of hereditary non-polyposis colorectal cancer.

Diagnosis of hereditary non-polyposis colorectal cancer (HNPCC) is currently based on phenotypical analysis of an expanded pedigree. Diagnostic guidelines ('Amsterdam criteria') proposed by the International Collaborative Group on HNPCC are often too stringent for use with small families. There is also the possibility of false-positive diagnosis in large pedigrees that may contain chance clusters of tumours. This study was conducted to determine the effect of family size on the probability of diagnosing HNPCC according to the Amsterdam criteria. A total of 1052 patients with colorectal cancer were classified as HNPCC or non-HNPCC according to the Amsterdam criteria. Associations between this diagnosis and the size of the first-degree pedigree were evaluated in logistic regression and linear discriminant analyses. Logistic regression showed a significant association for family size with the Amsterdam-criteria-based HNPCC diagnosis. Linear discriminant analysis showed that HNPCC diagnosis was most likely to occur when first-degree pedigrees contained more than seven relatives. Failure to consider family size in phenotypic diagnosis of HNPCC can lead to both under- and overestimation of the frequency of this disease. Small pedigrees must be expanded to reliably exclude HNPCC. Positive diagnoses based on assessment of eight or more first-degree relatives should be supported by other clinical features.

Adult↗

PubMed1995

Effect of intensive treatment on diabetic nephropathy in patients with type I diabetes.

We evaluated the long-term effect of an intensive treatment of diabetic nephropathy (anti-hypertensive drugs, low protein diet, multiple insulin injections to achieve a good metabolic control) on glomerular filtration rate (GFR) and albumin excretion rate (AER). Fourteen type I diabetic patients (mean age 45 +/- 9.5 years, mean duration of diabetes 23.5 +/- 7.3 years, 8 males/6 females) with glomerular filtration rate < 70 ml/min-1/1.73 m2 and albumin excretion rate > 30 micrograms/min were treated intensively for 36 months. This intensive treatment consisted of multiple insulin injections, antihypertensive therapy with ACE inhibitors and a low-protein diet (0.8 g/kg body wt/day.) Renal function was evaluated as GFR and AER. HbA1c mean value decreased significantly from 8.7 +/- 0.8% to 6.5 +/- 0.5% (P < 0.0002). GFR rose from 58 +/- 12 ml/min-1/1.73 m2 to 84 +/- 11 ml/min-1/1.73 m2 (P < 0.0008). AER decreased from 208 micrograms/min (range: 73 to 500) to 63.8 micrograms/min (range 15 to 180; P < 0.05). Systolic and diastolic blood pressure decreased respectively from 144 +/- 26 mm Hg to 120 +/- 15 mm Hg and from 89 +/- 9 mm Hg to 75 +/- 8 mm Hg (P < 0.01). We obtained a rise of GFR and a reduction of proteinuria after three years of this treatment. We suggest that this intensive treatment in all patients with early stage diabetic nephropathy may be effective in slowing the progression to renal failure.

Adult↗

PubMed1995

Acute pyelonephritis as a cause of hyponatremia/hyperkalemia in young infants with urinary tract malformations.

Obstructive uropathy causes tubular resistance to aldosterone and severe metabolic imbalance may be precipitated by an episode of pyelonephritis. In the last 3 years we investigated 52 episodes of pyelonephritis (positive urine culture, elevated C reactive protein, fever, elevated neutrophil count) in 50 children between 15 days and 15 months of age. Ultrasonography voiding cystography and renal scintiscan were performed in all cases and i.v. urography in some. A salt-losing syndrome with hyponatremia and hyperkalemia (Na < 125 meq/liter; K > 6.3 meq/liter) was observed in 17 infants < 3 months, accompanied by plasma aldosterone concentration of 5000 to 23,000 pg/ml (normal value, < 1000 pg/ml). All these children had a severe urinary tract (UT) malformation (ureteropelvic junction stenosis in 7 cases, vesicoureteral reflux in 7, posterior urethral valves in 2, double system in 1). Thirteen infants < 3 months, 7 with no urinary tract malformations, did not have electrolyte imbalance. Pyelonephritis was diagnosed in 20 other patients ages 4 to 15 months, including 16 with severe UT malformations; 4 had normal UTs. We conclude that a salt-losing syndrome with tubular resistance to aldosterone can occur during pyelonephritis in young infants with congenital UT malformation, that the risk diminishes considerably or disappears after 3 months of age and that in the absence of UT malformation pyelonephritis does not cause acute sodium loss of clinical relevance.

Age Factors↗

PubMed1995

Lactate dehydrogenase activity of platelets in diabetes mellitus.

Lactate dehydrogenase (L-lactate : NAD+ oxidoreductase, EC 1.1.1.27) activity has been measured on the subpopulations of platelets obtained from blood of diabetic patients. Small, but not large platelets show a lactate dehydrogenase activity higher than that of controls. Moreover, a positive statistically significant correlation was found between the activity of small platelets and the percent of glycated haemoglobin, while no correlation was obtained in the case of large platelets. Since we previously demonstrated that lactate dehydrogenase activity of small platelets is exceedingly high in some clinical and experimental conditions, our results not only confirm the involvement of platelets in diabetes but provide more evidence in support of our previous hypothesis of a relationship between lactate dehydrogenase and in-vivo platelet activation.

Adult↗

PubMed1994

Role of clinical criteria in the diagnosis of hereditary non-polyposis colorectal cancer (HNPCC): results of a multivariate analysis.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disease characterized by early-onset colorectal tumors, primarily in the right colon, that are frequently associated with other cancers. In the absence of a reliable biomarker, clinical criteria for diagnosing HNPCC have been proposed by the International Collaborative Group on HNPCC (ICG-HNPCC). However, these criteria are often too restrictive for application in small families. We analyzed 6 clinical/pathological features suggestive of genetic colon-cancer risk in 970 colorectal-cancer patients defined according to the ICG criteria as HNPCC (96) or non-HNPCC (874). Logistic regression analysis was used to determine their relative potentials for predicting the diagnosis of HNPCC. The most predictive were then used to estimate HNPCC risk levels within the non-HNPCC group. Multivariate analysis showed the following associations with HNPCC diagnosis: vertically transmitted cancer ("highly predictive"), early-onset (< 50 yrs) colorectal cancer, aggregation of tumors in the nuclear pedigree and proximal-colon tumors (the last 3 considered "predictive"). Re-evaluation of all families revealed that 76 non-HNPCC families (8.9% of the whole series) satisfied our highly predictive vertical-transmission criterion plus at least one of the other "predictive" criteria. The presence of 2 consecutive generations affected by colorectal cancer or early primaries seems to be a major risk indicator of hereditary colorectal cancer. Using this approach we identified a large group of families that require further evaluation, although they do not currently meet the ICG-HNPCC criteria for HNPCC.

Colorectal Neoplasms, Hereditary Nonpolyposis↗

PubMed1994

DNA ploidy pattern in human chronic liver diseases and hepatic nodular lesions. Flow cytometric analysis on echo-guided needle liver biopsy.

BACKGROUND: Significantly elevated fractions of diploid hepatocytes and reduction in the polyploid populations have been reported in human and experimentally induced hepatocellular carcinomas (HCC). This study was conducted to determine how these changes are related to conditions that often precede HCC, such as chronic hepatitis, cirrhosis, and premalignant focal nodules in cirrhotic livers. METHODS: Ultrasound-guided needle biopsy specimens of the liver were obtained from patients with chronic hepatitis, cirrhosis, or ultrasonographically diagnosed nodules within cirrhotic livers; biopsy specimens also were taken from patients without hepatic disease. DNA flow cytometry was performed on isolated nuclei to determine the percentages of diploid, tetraploid, and octaploid hepatocytes; the S-phase fraction for each diploid peak and the diploid/polyploid (tetraploid + octaploid) ratio also were calculated. Part of each specimen was reserved for evaluation of hepatocyte binuclearity. RESULTS: Chronically hepatitic (18 patients) and cirrhotic (18 patients) livers showed significantly increased diploid/polyploid ratios, with respect to normal livers, that were significantly correlated with decreases in hepatocyte binuclearity. This trend was even more marked in euploid nodules (4 premalignant and 5 malignant), in which the S-phase fractions were significantly higher than those of normal liver; aneuploidy was found in 6 of 11 malignant and 2 of 6 premalignant nodules.

Aged↗

PubMed1994

Extradural haematoma. Report of 37 consecutive cases with survival.

The availability of CT scanning has considerably improved the results in patients with extradural haematoma (EDH). However, only few reports referred the "zero-mortality" which today could be considered as possible. This goal was achieved by us recently even in those patients suffering from rapidly developing EDH. A series of 37 consecutive patients with EDH operated on during the last years is presented. 27 patients were comatose GCS 3-8 on admission (within 6 hours after the injury) and underwent surgery immediately; in 7 cases the operation was performed 6 to 25 hours after the injury, soon after the worsening of the level of consciousness; 3 patients were awake at time of surgery and were operated on later than 24 hours after the injury when signs of neurological deterioration appeared. All of our patients survived and 35 of them (95%) fully recovered. We believe that the duration of brain compression is the main factor strongly correlated with outcome. Therefore, in our opinion the primary prerequisite in order to obtain a good result is the prompt evacuation of EDH; furthermore, in this was it is possible to try to prevent brain ischaemia due to clot pressure, mostly the infarction on deeply situated territories.

Adolescent↗

PubMed1994

Circadian variations of epithelial cell proliferation in human rectal crypts.

BACKGROUND/AIMS: Evidence (almost exclusively from animal studies) suggests that proliferation within the colorectal mucosa undergoes circadian variations. The epithelial cells that line the human colorectal crypt occupy definite positions along the longitudinal axis according to their proliferative potential and degree of differentiation. Thus, circadian rhythmicity was investigated in humans to locate the areas along the longitudinal crypt axis in which diurnal fluctuation might occur. METHODS: Rectal mucosal biopsy specimens were obtained every 4 hours for a 24-hour span from each of 23 subjects (8 healthy volunteers and 15 with histories of sporadic adenomatous polyps). [3H]thymidine histoautoradiography was used to determine ratios of S-phase to total cells (total labeling index) in the crypt. Glands were also divided into 5 equal compartments from base (compartment 1) to mouth (compartment 5), and labeling indices were calculated for each. RESULTS: Important temporal variations were confined to compartment 2 (F = 5.15, P = 0.0003) and total labeling indices (F = 3.57, P = 0.005). Despite individual variations, proliferation was generally higher at night and lower during afternoon. Upper-crypt proliferative rates (compartments 4 and 5) remained decidedly stable (F = 0.5, P = NS). Normal subjects and patients with polyps displayed similar circadian behaviors. CONCLUSIONS: Circadian fluctuation in proliferation is confined to the area of the crypt normally associated with replication. Upper-crypt indices, including those that were higher than normal (a colon-cancer risk marker) are stable over 24 hours. These findings should be useful in planning chemoprevention trials and chemotherapeutic regimens.

Adult↗

PubMed1994

Effects of different doses of fish oil on rectal cell proliferation in patients with sporadic colonic adenomas.

BACKGROUND/AIMS: Fish oil supplementation can reduce cytokinetic anomalies in the flat rectal mucosa of patients with sporadic colorectal adenoma. This study attempted to identify an optimum dose for fish oil supplementation and evaluate the persistence of its effects during long-term administration. METHODS: In a double-blind study, 60 patients with sporadic adenomas received 2.5, 5.1, or 7.7 g of fish oil per day or placebo for 30 days. [3H]thymidine autoradiographic labeling indices were calculated in flat rectal mucosal biopsy specimens collected before and after supplementation. In a subsequent study, 15 patients with polyps received 2.5 g of fish oil per day. Proliferative parameters, mucosal fatty acids, and mucosal and plasma alpha-tocopherol levels were evaluated before, during, and after 6 months of supplementation. RESULTS: Mean proliferative indices and mucosal arachidonic acid levels decreased significantly (and to similar degrees) in all treated groups, whereas mucosal eicosapentaenoic and docosahexaenoic acid levels increased. Significantly reduced proliferation was observed only in patients with abnormal baseline patterns. These effects persisted during long-term, low-dose treatment. A transient reduction in mucosal (but not plasma) alpha-tocopherol levels was observed after 1 month of treatment. Side effects were insignificant. CONCLUSIONS: Low-dose fish oil supplementation has short-term and long-term normalizing effects on the abnormal rectal proliferation patterns associated with increased colon cancer risk.

Adenomatous Polyposis Coli↗

PubMed1994

Congenital renal damage associated with primary vesicoureteral reflux detected prenatally in male infants.

To assess the course of vesicoureteral reflux, we performed cystography, renal scintigraphy, and urography in all neonates with the prenatal diagnosis of renal pelvic dilation and revealed the presence of primary reflux (grades I to V) in 27 cases. Higher grades of reflux were associated with congenital renal damage, as shown by reduced tracer uptake during scintigraphy. Reflux was diagnosed more frequently in male infants (male/female ratio, 6:1), in many of whom bladder abnormalities were found by cystography. In another group of seven infants, in whom the reflux was associated with other urologic abnormalities, there was no sex prevalence. We conclude that severe primary reflux associated with hydronephrosis usually affects male infants and may be due to abnormal embryologic development of the male urethra, and that the kidney damage is primary and not the result of urinary tract infections. This pattern differs from that of vesicoureteric reflux diagnosed at an older age, which is observed most commonly in female patients.

Female↗

PubMed1994

Cowden's disease with extensive gastrointestinal polyposis.

Cowden's disease, or multiple hamartoma syndrome, is a rare condition classified recently as a hereditary preneoplastic syndrome. Multiple orocutaneous hamartomas are associated with involvement of other organ systems, including fibrocystic breast disease and breast carcinoma, goiter, thyroid cancer, gastrointestinal polyps, and endometrial carcinoma. We describe a patient with Cowden's disease who underwent extensive gastroenterological work-up and review other cases in the literature.

Adenomyoma↗

PubMed1994

Mild fetal hydronephrosis indicating vesicoureteric reflux.

The management of neonates with mild hydronephrosis diagnosed antenatally is still debated. Although some of these infants are normal, it is recognised that others will have mild obstruction of the ureteropelvic junction or vesicoureteric reflux (VUR). A prospective study was performed in all newborn infants with an antenatal diagnosis of mild hydronephrosis (47 babies, 62 kidneys) born over a two year period in order to assess the frequency of VUR. Voiding cystography in 14 patients with 21 renal units showed VUR. Two patients underwent surgery and the VUR resolved; the other 12 received medical treatment. Repeat cystography was scheduled for 12-18 months later, when a high rate of spontaneous cure was observed. The remaining patients were monitored by ultrasonography but only in one case did hydronephrosis deteriorate because of the presence of severe ureteropelvic junction obstruction. It is concluded that mild dilatation of the pelvis might be an expression of a potentially severe malformation such as VUR, and a careful follow up of these cases is mandatory.

Female↗

PubMed1994

Reliability of rectal epithelial kinetic patterns as an intermediate biomarker of colon cancer.

The use of biomarkers to assess cancer risk is based on the model of cancer as a multistep process; such markers are assumed to reflect an early stage in this process. A valid biomarker of risk must therefore show differential expression in normal and high-risk subjects, as well as quantitative correlation with the stage of carcinogenesis. It should also be easy to detect in small tissue specimens and responsive to modulation by chemopreventive agents. Cell proliferation is one of the most widely investigated markers of cancer risk. Case-control studies have shown that epithelial cell proliferation parameters, assessed in rectal mucosal biopsies by means of in vitro autoradiographic or immunohistochemical techniques, can discriminate between populations with normal and high risks for colon cancer. However, we recently reviewed rectal biopsies from 152 subjects (43 controls, 84 with adenomas, 25 resected for colon cancer) processed for in vitro 3H-thymidine autoradiography, and attempted to correlate various proliferative parameters with clinical and pathological variables by means of multiple regression analysis. Elevations of total crypt labeling indices (LIs), particularly upper crypt LIs, were significantly associated with the presence of adenomatous polyps, although subsequent linear discriminant analysis revealed that the accuracy of LIs in discriminating between polyp patients and controls was actually quite low. However, we have also found that upper crypt LIs are reliable predictors of adenomatous polyp recurrence. Repeated evaluations of rectal proliferative indices over a 2-year post-polypectomy follow-up of 40 patients with colonic adenomas revealed substantial stability.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma↗

PubMed1993

Urinary kallikrein excretion in type 1 (insulin-dependent) diabetes mellitus.

Kidney haemodynamics appear to change after the early phases of diabetic nephropathy: increases in glomerular filtration rate and in renal plasma flow have been widely reported, while kidney size is increased. As the renal kallikrein-kinin system has been demonstrated to regulate kidney blood circulation, we have evaluated the excretion of urinary kallikrein in 87 Type 1 (insulin-dependent) diabetic patients with and without hyperfiltration. Urinary kallikrein excretion was measured in 24-h urine collections. The esterolytic activity was determined by fluorimetric assay. The excretion of urinary kallikreins was significantly higher in hyperfiltering patients (472 +/- 125 esterase units/24 h) than in normofiltering (168 +/- 77 esterase units/24 h) and control subjects (151 +/- 39 esterase units/24 h), p < 0.001. Furthermore, we observed a positive correlation between urinary kallikrein excretion and glomerular filtration rate (r = 0.785). These data suggest that variations of kallikrein and kinin concentrations may play a role in the alteration of renal haemodynamics in Type 1 diabetes. It is possible that the kinin-kallikrein system, the renin-angiotensin system and the prostaglandins may interact to determine the haemodynamic alterations which are present in the diabetic disease.

Adult↗

PubMed1993

n-3 PUFA and alpha-tocopherol control of tumor cell proliferation.

Subjects at high risk for colon cancer received different doses of fish oil on a 30-day randomized double-blind trial to evaluate the chemopreventive effect of n-3 fatty acids against colorectal cancer. Using rectal mucosal proliferation, assessed with 3H-thymidine autoradiography, fish oil induced in the treated groups but not in the placebo group a change in the proliferative pattern, which resulted similar to that observed in low risk population; in the same groups rectal mucosal n-3 fatty acid content increased, where arachidonic acid level decreased. Moreover, n-3 PUFA treatment induced modifications of Vitamin E status. The results suggest that n-3 PUFA could protect high-risk subjects from colon cancer by a mechanism involving a modulation of Vitamin E.

Adenomatous Polyposis Coli↗

PubMed1993

Rectal epithelial cell proliferation patterns as predictors of adenomatous colorectal polyp recurrence.

To determine whether proliferative patterns in flat rectal mucosal samples can predict the recurrence of adenomatous colorectal polyps, after polypectomy, biopsy specimens from normal looking rectal mucosa were obtained at endoscopy from 55 patients diagnosed for the first time as having adenomatous colorectal polyps. Epithelial cell proliferation was assessed in biopsy specimens through 3H-thymidine autoradiography. After polypectomy, patients were followed for 24 months and underwent complete colonoscopy every 6 months to detect and remove any metachronous lesions. In 40 patients second biopsy specimens were taken during one of the follow up colonoscopies to evaluate the stability of proliferative indices over time. The ratio of labelled (S phase) to total cells (labelling index) for the entire crypt, as well as ratios for each of the five equal compartments into which the crypt had been divided longitudinally, was calculated for each patient. Mean labelling indices for upper crypt compartments 3 and 4 + 5 in the 22 patients in whom polyps recurred were significantly higher (respectively p < 0.05 and p < 0.01) than those of the 33 without recurrence suggesting that an upward shift of the crypt's replicative compartment is associated with polyp recurrence. Labelling indices remained essentially unchanged in those patients who underwent biopsy twice. Reproducible kinetic parameters such as these might be useful in planning follow up of patients with adenomatous polyps after polypectomy.

Adult↗

PubMed1992

Effect of omega-3 fatty acids on rectal mucosal cell proliferation in subjects at risk for colon cancer.

The effects of 12 weeks of omega-3 fatty acid supplementation on rectal mucosal proliferation were assessed with [3H]thymidine autoradiography in a double-blind, placebo-controlled study of 20 patients with sporadic adenomatous colorectal polyps. In the group of 10 that received fish oil containing eicosapentaenoic acid (4.1 g/day) and docosahexaenoic acid (3.6 g/day), the mean percentage of replicative "S"-phase cells in the upper part of colonic crypts (considered a reliable marker of colon cancer risk) significantly dropped from the baseline level after only 2 weeks of treatment and remained lower throughout the study period; no change in upper-crypt labeling was observed in the 10 placebo patients. Rectal mucosal eicosapentaenoic acid content increased in fish oil patients, whereas arachidonic acid levels decreased. The fish oil-induced kinetic changes represent contraction of the proliferative compartment to the levels of a low-risk population and may be related to omega-3 fatty acid effects on the arachidonic prostaglandin pathway. In this short-term trial, fish oil appeared to exert a rapid effect that may protect high-risk subjects from colon cancer.

Autoradiography↗