Characterization of a lung epithelium specific E-cadherin knock-out model: Implications for obstructive lung pathology.

The airway epithelium regulates responses to aeroallergens, acting as a physical and immunological barrier. In asthma, epithelial barrier function and the expression of adherens junction protein E-cadherin is compromised, but it is unknown whether this is cause or consequence of the disease. We hypothesized that airway epithelial loss of E-cadherin is a critical step in the development of manifestations of asthma. We generated a transgenic mouse model with conditional loss of E-cadherin in lung epithelial cells at birth and onwards. We observed normal lung development at the time of birth in mice lacking E-cadherin in the lung epithelium. However, E-cadherin deficiency led to progressive epithelial damage in mice growing into adulthood, as evidenced by airway epithelial denudation, decreased zonula occludens (ZO)-1 expression, loss of ciliated cells, and enlarged alveolar spaces. In addition, spontaneous goblet cell metaplasia with mucus production was observed. These epithelial changes were accompanied by elevated levels of the epithelial-derived chemokine CCL17, infiltration of eosinophils and dendritic cells, and mucus production. In conclusion, loss of E-cadherin induces features in the lung reminiscent of those observed in asthma, indicating that the disruption of E-cadherin-mediated cell-cell contacts may play a key role in the development of asthma manifestations.

Pre-operative staging of rectal cancer using multi-detector row computed tomography with multiplanar reformations: single center experience.

BACKGROUND: Technical advancement in imaging has helped to stage and plan treatment modality for carcinoma rectum with still some objectives controversial. AIMS: The aim of our study was to evaluate the accuracy of multidetector row computed tomography (MDCT) with multiplanar reformations in the pre-operative staging of rectal carcinoma and correlation with intraoperative and histopathologic staging of retrieved specimen with respect to the depth of tumor invasion (T-staging), lymph node metastasis (N-staging) and mesorectal fascia (MRF) involvement. MATERIALS AND METHODS: The study was a prospective one and consisted of 52 patients with biopsy proved rectal carcinoma. MDCT studies were performed on a 64-slice computed tomography system. Images were reconstructed in axial, coronal and sagittal planes. MDCT findings were compared with intraoperative and pathologic (reference standard) findings. Sensitivity, specificity, positive predictive value, negative predictive value and accuracy were assessed. RESULTS: The diagnostic accuracy of MDCT for T1/T2, T3 and T4 lesions was 77%, 86.5% and 100%, respectively. For perirectal lymph node metastasis (N+), the diagnostic accuracy of MDCT was 84.1%. The diagnostic accuracy of MDCT for MRF involvement was 91%. CONCLUSION: MDCT is a reliable radiological tool for local staging of rectal cancer with excellent accuracy rates for T and N-staging of rectal cancer.

Colonic J pouch neo-rectum versus straight anastomosis for low rectal cancers.

AIM: The development of sphincter saving procedures for low carcinoma rectum has been the consequence of oncological and technological factors. The major disadvantage associated with these procedures is the development of anterior resection syndrome because of the resection of rectal reservoir. Colonic J pouch (CJP) neorectum has been practiced as an antidote to overcome this problem. We are working at a tertiary care center, which is a high volume center for rectal cancers. We thought it worthwhile to assess the efficacy of J Pouch neorectum viz.-a-viz. a straight coloanal anastomosis for low rectal cancers. MATERIALS AND METHODS: Hospital based prospective randomized study (June 2007-December 2009) low rectal cancers (4-12 cm from the anal verge). One group (20 patients) subjected to low/ultralow anterior resection with straight anastomosis (SA) and other group (22 patients) to CJP. The two groups were compared on the basis of functional outcome. RESULTS: Anastomotic leak, strictures, frequency of bowel movements, nocturnal bowel movements, use of retarding medication and incontinence to solids, liquids and gases were seen more in SA group. All these findings were statistically significant. CONCLUSIONS: We conclude that CJP has a significant functional advantage over SA and improves the overall quality-of-life in patients of low rectal cancers and the advantage persisted over a period of more than 30 months.

Pregnenolone derivatives as potential anticancer agents.

Pregnenolone (1) was used as a template to develop new anticancer compounds. Ring-D modification of 1 resulted in the synthesis of benzylidenes 2-17, pyrazolines 18-76, pyrazoles 85-91, hydrazones 77-84, and oximes 92-107 derivatives. The structure of compound 107 was also deduced through single crystal X-ray diffraction studies. The inclusion of furanyl and pyridyl rings to pregnenolone skeleton increases the cytotoxicity of all compounds significantly. Among benzylidene derivatives, only heterocyclic enone 8 (IC50=0.74 µM/mL against HepG2), and 17 (IC50=4.49 µM/mL against HepG2, IC50=5.01 µM/mL against MDA-MB-230 cancer cell line) exhibited a significant activity. The cytotoxicity data of pyrazoline derivatives 18-76 revealed that only furanyl bearing pyrazolines 40, 42-44, 48, and 49 exhibited significant activities. While all (O-carboxymethyl) oximes, hydazones, and pyrazoles derivatives of pregnenolone did not show any significant activity against both the cell lines. Thus the furanyl bearing enone 8 (IC50=0.74 µM/mL against HepG2), and its pyrazoline derivative 48 (IC50=0.91 µM/mL against MDA-MB-230 cancer cell lines) were identified as the most active compounds in all derivatives of pregnenolone.

Color Doppler findings of post-biopsy arteriovenous fistula in renal transplant.

Post biopsy arterio-venous fistula in renal transplant range in incidence from 15-16%. Spontaneous resolution of 75% A-V fistulas is seen within four weeks. We report a patient with post biopsy arterio-venous fistula who had developed unexplained hypertension with no definite feature of rejection on biopsy. Doppler application revealed an arterio-venous fistula which showed spontaneous resolution in six weeks.

The new rHuEPO alpha (epotin) in the management of anemia of end-stage renal disease in patients on maintenance hemodialysis.

Recombinant human erythropoietin has proved to be effective to treat anemia of end-stage renal disease (ESRD). The aim of this study was to assess the efficacy and safety profile of Epotin, a rHuEPO produced in the Middle East. One hundred thirty patients with Hct

Posttransplant complications encountered in renal transplantation in the Middle East.

This paper discusses the commonly seen complications encountered in Middle Eastern transplant recipients, including posttransplant Kaposi's sarcoma, tuberculosis, infective diarrhea, and pregnancy.

Steroidal alkaloids from the leaves of Sarcococca coriacea of Nepalese origin.

Two new steroidal alkaloids, (-)-vaganine D (1) [(20S)-20-(N,N-dimethylamino)-3 beta-(senecioylamino)-5 alpha-pregn-16-en-4 beta-yl acetate], and (+)-nepapakistamine A (2) [(20S)-20-(N-methylamino)-3 beta-(tigloylamino)-5 alpha-pregn-16-en-2 beta,4 beta-diacetate], were isolated from the leaves of Sarcococca coriacea. Their structures were elucidated on the basis of their spectral properties. Compounds 1 and 2 were found to be cholinesterase inhibitors.

Hypercholesterolemia in renal transplantation.

OBJECTIVES: We conducted this study to evaluate the prevalence, and risk factors of hypercholesterolemia (HC) in renal transplant population. METHODS: We reviewed the records of the active renal transplant patients at two large transplant centers in Riyadh and Jeddah in Saudi Arabia transplanted between 1979 and November 1998. The patients were grouped according to the measurement of serum cholesterol level; group I (normal): below or equal 5.2 mmol/L, group II (mild HC): from 5.3-6.0 mmol/L, group III (moderate HC): from 6.1-8.0 mmol/L group IV (severe HC): above 8.0 mmol/L. RESULTS: There were 1096 patients' records included in the study. According to the level of measured serum cholesterol, there were 421 (38.4%) patients is group I, 256 (23.3%) patients in group II, 363 (33.1%) patients in group III and 57 (5.2%) patients group IV. We found no significant difference between the study groups in terms of gender (60% males, 40% females), mean duration of transplantation (66.9 months), between those transplanted before 1990 and those transplanted after 1990, donor type, prevalence of hypertension (85%), history of hypertension on dialysis, original kidney disease, frequency of rejections in the first year (28%), mean serum creatinine (220 mumol/L), cyclosporine mean dose (3.2 mg/kg/day) mean prednisone dose (0.15 mg/kg/day), number of patients on azathioprine (65%), the mean proteinuria (0.6 G/L) or number of antihypertensives. In comparison with the group with normal serum cholesterol level, the group with severe hypercholesterolemia had significantly higher mean age (40.6 versus 37.4 years), higher mean weight (72 versus 65.8 kg), rate of retransplantation (8.8% versus 3.1%), higher frequency of diabetics (35% versus 20%) and higher frequency of abnormal electrocardiogram (18.2% versus 5.2%). CONCLUSION: That hypercholesterolemia is a significant problem in the renal transplant population in Saudi Arabia. Risk factors for the development of hypercholesterolemia are mainly related to weight, age, diabetes and retransplantation.

The spectrum of glomerulonephritis in saudi arabia: the results of the saudi registry.

Only few studies regarding glomerulonephritis, with relatively small numbers of patients, have so far been published from different centers in Saudi Arabia, and have reported conflicting results regarding the patterns, even in the same city. The possible reasons for these differences include the small number of patients in the different studies, differences in the indications for renal biopsies, referral bias, geographical differences, and, sometimes, the non-availability of the necessary diagnostic facilities in the reporting centers. In order to overcome these problems, a registry for glomerulonephropathy was attempted in Saudi Arabia. Six large referral hospitals from different regions of Saudi Arabia participated in this registry. Biopsy reports and clinical information of 1294 renal biopsies were obtained. There were 782 renal biopsies due to glomerulonephritis (GN) accounting for 77.2% of the total biopsies. Five hundred eighty seven (72.6%) were primary glomerulonephritidis. Focal and segmental glomerulosclerosis (FSGS) (21.3%) and membrano-proliferative glomerulonephritis (MPGN) (20.7%) were the most common types found in the primary glomerulonephritidis. Membranous glomerulonephritis (MGN) was present in only 10.6% of the cases. IgA nephropathy was found in 6.5% of the cases. Of the secondary glomerulo-nephritides, systemic lupus erythematosus (SLE) was the most common indication for biopsy (57.0%) and amyloidosis was found in only 3.2% of the biopsies. In conclusion, FSGS and MPGN were the most common forms of primary glomerulonephritis in adult patients in Saudi Arabia. MGN was not as common as in the western world. SLE was the commonest cause of secondary GN. Amyloidosis was not as common as in other Arab countries. There is a need for more centers from Saudi Arabia to join this national GN registry. Similar registries can be established in different Arab countries, which all would, hopefully, lead to a Pan-Arab GN registry.

Acute Renal Failure and HELLP Syndrome: A Single Center's Experience.

A total of 52 patients were referred to our center from gynecology and obstetric units in our area with acute renal failure during the last two years. Seven patients were found to have so called syndrome of hemolysis (H), elevated liver enzymes (EL) and low platelets (LP) associated with acute renal failure. The syndrome can easily be confused with other diagnoses like hemolytic uremic syndrome, idiopathic thrombotic thrombocytopenic purpura and disseminated intravascular hemolysis. Six patients had renal biopsies to confirm the diagnosis, while one did not consent for biopsy. Four patients were found to have acute tubular necrosis, one had acute cortical necrosis and one was not enough for interpretation. We conclude that the patients can easily be misdiagnosed if we are not familiar with the diagnosis and that the overall prognosis is good if the patient survives the acute stage.

Opinion Survey about the Evaluation and Management of Acute Renal Failure in Saudi Arabia.

To evaluate the approach of physicians to the diagnosis and management of acute renal failure (ARF) in the Kingdom of Saudi Arabia, a questionnaire was mailed to nephrologists, physicians attending to renal failure patients, specialists working in intensive care unit (ICU) and the general physicians in 110 hospitals, which have either an ICU or a dialysis unit. The questions were related to the areas of evaluation, conservative management, dialysis therapy, and prognosis of ARF. There were 135 responses from 76 hospitals (69%); 37 of small size (< 150 beds), 21 of medium size (151-400 beds), and 18 of large size (401-1200 beds). There were 69 respondents from the small hospitals, 34 from the medium-sized, and 32 from the large hospitals. According to the respondents, the most encountered ARF patients were in the intensive care units and were most likely due to sepsis and nephrotoxic drugs. There were no differences among the respondents in the areas of initial evaluation, conservative and/or emergency treatment. However, the nephrologists were significantly more willing to follow-up their ARF patients and to carry more specific diagnostic procedures (i.e., renal biopsy) and specific advanced therapeutic procedures (i.e., dialysis), More ARF patients are being treated by continuous renal replacement therapy (CRRT) than intermittent hemodialysis or peritoneal dialysis. The minority of the respondents believed that the prognosis of ARF had not improved much, despite the improvement in diagnosis and therapy. They attributed this to the change in the demographics of ARF, since more ICU and elderly patients are seen in practice. We conclude that nephrologists are indispensable for the management of acute renal failure. More efforts may be needed to recruit nephrologists to hospitals in Saudi Arabia. A local fellowship program may help in this regard. Furthermore, CRRT facilities, at least in the large hospitals, are required.

Percutaneous renal biopsy and its findings in children and adolescents in saudi arabia: a single center experience.

A retrospective study of 108 consecutive renal biopsies in children and adolescents below 18 years of age performed at the King Fahd Hospital, Jeddah, during an eight-year period ending 1996, was made. All the biopsies were performed by a single consultant nephrologist and under ultrasound guidance. Tru-cut needles were employed in all cases and in the last two years, the bioptic gum was used. The age of the patients ranged between 3 months and 18 years with a mean of 10.6 years. There were 58 males and 50 females. All patients tolerated the biopsy well and there were no failures. The common side effects noted included gross hematuria in three (2.8%) and severe pain at the biopsy site in 11 (10.2%). None of the patients needed blood transfusions or prolonged hospitalization. Nephrotic syndrome was the commonest indication for performing the biopsy (83.3%) and among them, minimal change was the commonest lesion found (25%) followed by focal and segmental glomerulosclerosis (14.8%) and mesangial proliferative glomerulonephritis (15.7%). Our study further shows that renal biopsy is a safe procedure in children and the commonest indication is nephrotic syndrome.

Kaposi's sarcoma in renal transplant recipients.

One hundred and seventeen of 270 (43%) recipients of organs obtained from donors with malignancies had evidence of transmitted cancers. In 9 instances these were removed from renal allografts immediately prior to transplantation. Including these cases there were 45 recipients of organs in which a neoplasm involved the allograft, 6 others in whom adjacent structures were invaded, and another 66 patients who had distant metastases. Precautions to prevent cancer transmission include meticulous preoperative screening of donors, careful examination of all organs at the time of harvesting, biopsy of any suspicious lesions, and routine donor autopsy, if possible.

Is aluminum related bone disease common in hemodialysis units using aluminum based phosphate binders?

The extent of aluminum related bone disease was evaluated in 41 patients on regular maintenance hemodialysis in two dialysis centers in Riyadh, Saudi Arabia. There were 22 males and 19 females aged 20 to 70 years (mean 35.5+11.2 years). Thirty eight of the patients were on aluminum based oral phosphate binders. Investigations performed included serum calcium, magnesium, aluminum and parathormone and radiological investigations including skeletal survey and dual photon absorptiometry. All the patients underwent bone biopsy and the biopsy material was subjected to morphometric studies, including staining for aluminum deposits. The patients were divided into two groups: group 1, (16 patients, 39%) with negative aluminum staining in the bone biopsy tissue, and group 2, (25 patients, 61%) with positive aluminum staining. Bone pain and its distribution as well as fractures were similarly prevalent in both groups. The levels of aluminum in the blood was significantly higher in group 2 (32.9 + 20.2 vs 17.9 + 11.2 ug/L P< 0.05), though it was lower than the lowest accepted toxic level (40 ig/L). There was no significant difference between the two groups in the biochemical or hormonal data, frequency of abnormal radiological signs and pattern of bone histology. Our study indicates that increased aluminum deposition in the bone is prevalent in patients on maintenance hemodialysis using aluminum based phosphate binders, but adynamic bone disease is not prevalent. Further studies may be needed on a larger scale to assess the magnitude of the problem.

Transcatheter delivery of c-myc antisense oligomers reduces neointimal formation in a porcine model of coronary artery balloon injury.

BACKGROUND: Smooth muscle cell proliferation and extracellular matrix accumulation are the principal mechanisms leading to vascular restenosis. We have previously demonstrated the growth-inhibitory effect of antisense oligomers targeting the c-myc proto-oncogene in human smooth muscle cells. The goal of this study was to investigate whether c-myc antisense oligomers reduce neointimal formation in balloon-denuded porcine coronary arteries. METHODS AND RESULTS: First, type I collagen synthesis, which reflects synthetic function, was markedly reduced following c-myc antisense oligomers in porcine vascular smooth muscle cells independent of the growth inhibition. These effects in vitro provided the rationale for assessing c-myc antisense oligomers in the prevention of neointima in vivo. Second, the efficiency of single transcatheter delivery of oligomers into denuded porcine coronary arteries was determined. Despite rapid plasma clearance following local delivery, oligomers persisted at the site of injection for at least 3 days, exceeding by severalfold their concentration in peripheral organs. Third, morphometric analyses were carried out in balloon-denuded coronary arteries at 1 month after transcatheter c-myc antisense oligomer administration. Maximal neointimal area was reduced from 0.80 +/- 0.17 mm2 in the control group (n = 12) to 0.24 +/- 0.06 mm2 in the antisense-treated group (n = 13, P < .01). Likewise, a significant reduction in maximal neointimal thickness was observed in the antisense-treated group (P < .01). These changes in vascular remodeling following denuding injury resulted in an increase in residual lumen from 64 +/- 6% in the control group to 81 +/- 5% in the antisense-treated group (P < .05). CONCLUSIONS: (1) Single transcatheter administration allowed for endoluminal delivery of oligomers to the site of coronary arterial injury. (2) C-myc antisense oligomers reduced the formation of neointima in denuded coronary arteries, implying a therapeutic potential of this approach for the prevention of coronary restenosis. (3) It is postulated that the c-myc proto-oncogene is involved in the process of vascular remodeling, regulating smooth muscle cell proliferation and extracellular matrix synthesis.