Obesity: An Impact with Cardiovascular and Cerebrovascular Diseases.

The authors sought to correlate the complex sequel of obesity with various parameters known to develop metabolic syndrome viz. insulin resistance, dyslipidemia, hypertension etc., as these anomalies are linked to vascular atherosclerosis and outbreak of cardiovascular and cerebrovascular diseases.  A comprehensive online survey using MEDLINE, Scopus, PubMed and Google Scholar was conducted for relevant journals from 1970 till present time (2023) with key search terms like: 'obesity', 'leptin', type-2 diabetes', 'atherosclerosis', 'cardiovascular and cerebrovascular diseases'. The findings of the reports were compared and correlated. The information was then collated for developing this review. Reports showed that in human obesity, hyper-leptinemia could induce hyperglycemia, which in turn templates hypercholesterolemia. Persisting hypercholesterolemia over a period of time may en-route atherosclerosis in blood vessels. Thus obesity has been considered as a template for originating hyperglycemia, hypercholesterolemia and outbreak of vascular atherogenesis or in other words, obesity in long run can trigger atherosclerosis and its related disorders e.g. heart attack and stroke. Literature survey shows that primarily, co-morbidities of human obesity start with leptin and insulin resistance and then multiplies with metabolic irregularities to an extreme that results in pathogenesis of heart attack and stroke. Atherosclerosis associated cardiovascular and cerebrovascular events are independent risks of obese subjects and particularly in the cases of persisting obesity.

The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis.

OBJECTIVE: Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. METHODS: A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). RESULTS: Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo. CONCLUSIONS: Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response. TRIAL REGISTRATION NUMBER: NCT00976599.

Case Report: Urethral Diverticulum after Tubularised Incised Plate Repair of Distal Hypospadias: An Uncommon Complication.

Introduction: A urethral diverticulum can be defined as a pocket that forms from the lining of the urethra and protrudes into the surrounding tissue, a condition which causes voiding dysfunction and may result as a rare complication of hypospadias repair surgery. Case report: We report the case of a 2-year-old child who presented to us in 2019 complaining of a thin forceful stream, ballooning of the ventral aspect of the penis while voiding, and post-void dribbling. He has a history of undergoing a tubularised incised plate urethroplasty for distal penile hypospadias at 18-months-old. Ultrasound showed increased post-void residual volume and cystourethroscopy confirmed a urethral diverticulum extending from the subcorona to the base of the penis. The patient underwent partial excision of diverticulum, urethroplasty, and meatoplasty. He was followed-up 3 months later with complete resolution of his symptoms and a normal urinary stream with no urethral ballooning or dribbling. Conclusion: Urethral diverticulum may present as a complication post hypospadias repair. Although it is rare, we believe that it is important for the patient's parents to understand the possibility and know of the signs and symptoms in addition to attending regular outpatient clinic appointments in order to facilitate early management if needed. Furthermore, it is highly important for physicians to assess newborns for hypospadias before carrying out circumcision as it is a contraindication for the procedure.

Interpretation of chest fluoroscopy: the risk of misdiagnosing atelectasis as pneumothorax due to greyscale inversion.

Anaesthetists may be required to work in hybrid theatres for procedures using fluoroscopic imaging. Adequate knowledge of fluoroscopic images allows prompt and effective emergency management of complications which arise during procedures. Here, we present a case of severe hypotension and hypoxia occurring shortly after induction of anaesthesia. Atelectasis was mistaken for a pneumothorax due to misinterpretation of fluoroscopic imaging, which demonstrated a dark pleural cavity peripheral to a partially collapsed left lung, leading to an incorrect diagnosis. This case highlights the importance of understanding greyscale inversion in fluoroscopy.

Management of idiopathic granulomatous mastitis: a prospective study.

INTRODUCTION: Idiopathic granulomatous mastitis (IGM) is an evolving problem with varied presentation. No definite treatment guidelines are available at present that may reduce rate of recurrence. Current evidence suggests a ductal pathology behind IGM, which leads to periductal mastitis, leakage and sinus/fistula formation. Thus, excision of the sinus/fistulous tract with en-bloc wide local excision (WLE) of the lesion could be curative. The objective of this study was to look for the basic aetiology of IGM and evaluate the effectiveness of WLE with total or partial duct excision as a curative approach. METHODS: An institutional prospective comparative study was conducted over 4 years (2015-2019), in which 59 cases of IGM were randomly divided into three groups. After necessary investigations, patients in group A received steroid therapy, those in group B received WLE and patients in group C received WLE with total or partial duct excision as the mode of treatment. Postoperative follow-up was between 6 months and 3 years. RESULTS: Histopathological examination (HPE) was found to be the most suitable diagnostic procedure. Patients in group B showed the highest rate of recurrence (73.6%), followed by group A (35.0%) and group C (5.0%). Patients in group C had a significantly lower chance of recurrence compared with both group A and group B (p < 0.05). HPE reports of excised ducts from patients in group C showed ductal disruption and leakage along with periductal granuloma in 70% of cases. CONCLUSIONS: The presence of duct granuloma indicates the association of ductal pathology in IGM. IGM is therefore a disease of the mammary ducts and en-bloc duct excision is curative in non-responding cases.

5HT3 antagonists for prophylaxis of postoperative nausea and vomiting in breast surgery: a meta-analysis.

BACKGROUND: Postoperative nausea and vomiting (PONV) are distressing adverse events following breast cancer surgery with an incidence of up to 80%. 5HT 3 antagonists are commonly employed as drugs of first choice for PONV although there is no clear evidence favoring one pharmacological approach over another. AIMS: The objective of this meta-analysis is to compare the efficacy of 5HT 3 antagonists against all non-5HT 3 antagonism-based pharmacological approaches as a preemptive strategy for PONV in women undergoing breast surgery. DESIGN: Meta-analysis of Randomized Controlled Trials. MATERIALS AND METHODS: Literature search was conducted through PUBMED, reference lists, and Cochrane Central Register of Controlled Trials till June 2010 to identify eligible studies. Trials comparing 5-HT 3 antagonists with placebo or active controls for prophylaxis against PONV in women undergoing breast surgery were included. Two reviewers extracted the data independently. Methodological quality of each trial was assessed using Jadad score. RESULTS: Nineteen trials were included. All trials were of good methodological quality (Jadad score >3). 5HT 3 antagonists were found superior to placebo [Odds ratio (OR)=0.18 (0.13-0.26)] or active controls [OR=0.65 (0.47-0.91)] in the prevention of PONV. 5HT 3 antagonists were also superior to placebo in preventing nausea alone [OR=0.51 (0.34-0.76)], vomiting [OR=0.31 (0.20-0.47)] and the use of rescue antiemetics [OR=0.18 (0.11-0.28)]. No significant difference was observed in the use of rescue antiemetics as compared to active controls [0.59 (0.19 to 1.86)]. CONCLUSION: 5HT 3 antagonists are superior to other pharmacological interventions for the prevention of PONV in patients undergoing breast surgery under general anesthesia.

Unsterile injection equipment associated with HIV outbreak and an extremely high prevalence of HCV-A case-control investigation from Unnao, India.

The integrated counseling and testing center (ICTC) located in the district hospital, Unnao in the northern state of Uttar Pradesh (UP), India witnessed an increased detection of HIV among its attendees in July 2017. Subsequently, health camps were organized by the UP State AIDS Control Society in the villages and townships contributing to such detection. We conducted a case-control study to identify factors associated with this increased detection; 33 cases and 125 controls were enrolled. Cases were individuals, detected HIV sero-reactive during November 2017-April 2018 from three locations namely Premganj, Karimuddinpur and Chakmeerapur in the Bangarmau block of the district of Unnao. Controls hailed from the same geographical setting and tested HIV sero-nonreactive either in health camps or at ICTC centers from where the cases were detected. Misclassification bias was avoided by confirming HIV sero-status of both cases as well as controls prior to final analysis. Study participants were interviewed on various risk practices and invasive treatment procedures. They were also tested for HIV and other bio-markers reflecting unsafe injecting and sexual exposures such as hepatitis B surface antigen (HBsAg), anti-HCV antibody (HCV Ab), anti-herpes simplex-2 Immunoglobulin G (HSV-2 IgG) and rapid plasma regain (RPR) test for syphilis. Secondary data analysis on three time points during 2015 through 2018 revealed a rising trend of HIV among attendees of the ICTCs (ICTC-Hasanganj, ICTC-Unnao district hospital and ICTC- Nawabganj) catering to the entire district of Unnao. While there was a seven fold rise of HIV among ICTC attendees of Hasanganj (χ2 value for trend 23.83; p < 0.001), the rise in Unnao district hospital was twofold (χ2 value for trend 4.37; p < 0.05) and was tenfold at ICTC-Nawabganj (χ2 value for trend 5.23; p < 0.05) indicating risk of infection prevailing throughout the district. Primary data was generated through interviews and laboratory investigations as mentioned above. The median age of cases and controls was 50 year (minimum 18 -maximum 68; IQR 31-57) and 38 year (minimum 18 -maximum 78; IQR 29-50) respectively. Thirty six percent of the cases and 47% of controls were male. A significantly higher proportion of cases (85%) had HCV Ab compared to controls (56%; OR 4.4, 95% CI 1.5-12.1); none reported injection drug use. However, cases and controls did not differ significantly regarding presence of HSV-2 IgG (6% versus 8% respectively). Neither any significant difference existed between cases and controls in terms of receiving blood transfusion, undergoing invasive surgical procedures, tattooing, tonsuring of head or skin piercing. In multivariate logistic regression model, 'unsafe injection exposure during treatment-seeking'(AOR 6.61, 95% CI 1.80-24.18) and 'receipt of intramuscular injection in last five years' (AOR 7.20, 95% CI 1.48-34.88) were independently associated with HIV sero-reactive status. The monophyletic clustering of HIV sequences from 14 cases (HIV-1 pol gene amplified) indicated a common ancestry. Availability of auto-disabled syringes and needles, empowerment of the local communities and effective regulatory practices across care settings would serve as important intervention measures in this context.

ELAM-1 mediates cell adhesion by recognition of a carbohydrate ligand, sialyl-Lex.

Recruitment of neutrophils to sites of inflammation is mediated in part by endothelial leukocyte adhesion molecule-1 (ELAM-1), which is expressed on activated endothelial cells of the blood vessel walls. ELAM-1 is a member of the LEC-CAM or selectin family of adhesion molecules that contain a lectin motif thought to recognize carbohydrate ligands. In this report, cell adhesion by ELAM-1 is shown to be mediated by a carbohydrate ligand, sialyl-Lewis X (SLex; NeuAc alpha 2,3Gal beta 1,4(Fuc alpha 1,3)-GlcNAc-), a terminal structure found on cell-surface glycoprotein and glycolipid carbohydrate groups of neutrophils.

Clinico-epidemiological profile and high-risk sexual behavior among clients attending sexually transmitted infection clinic at a tertiary care hospital in North India.

CONTEXT: Sexually transmitted infections (STIs) are one of the most catastrophic events of health causing huge psychosocial and economic morbidity consequences. AIM: The study aims to study the clinico-epidemiological profile and high-risk sexual behavior among clients attending STI clinic at tertiary care hospital in North India. MATERIALS AND METHODS: The present study was conducted at STI clinic, King George's Medical University, Lucknow, Uttar Pradesh. Data from 1283 clients attending STI clinic between August 2015 and July 2016 were compiled using master client register and STI/reproductive tract infection patient-wise register, and a final completed data set of these patients was analyzed according to the aims and objectives. RESULTS: On analyzing the various factors associated with high-risk sexual behavior among clients attending STI clinic marital status, sexual preference and employment status were found to be significantly associated with high-risk sexual behavior (P < 0.05). On multivariate analysis, unmarried/divorced/widow/separated marital status (odds ratio [OR]: 14.72; 95% confidence interval [CI]: 1.89-114.17; P = 0.00) and unemployed status (OR: 6.10; 95% CI: 2.00-18.60; P = 0.02) were found to be independent predictors of high-risk sexual behavior (unprotected sex). CONCLUSIONS: Based on findings of study, it is highly recommended to provide periodic screening to these STI patients for assessment of their sexual behavior along with specific counseling session.

Antitumor immunity induced by laser immunotherapy and its adoptive transfer.

The ideal cancer treatment modality should not only cause tumor regression and eradication but also induce a systemic antitumor immunity, which is essential for control of metastatic tumors and for long-term tumor resistance. Laser immunotherapy using a laser, a laser-absorbing dye, and an immunoadjuvant has induced such long-term immunity in treatment of a mammary metastatic tumor. The successfully treated rats established total resistance to multiple subsequent tumor challenges. To further study the mechanisms of the antitumor immunity induced by this novel treatment modality, passive adoptive transfer was performed using splenocytes as immune cells. The spleen cells that were harvested from successfully treated tumor-bearing rats provided 100% immunity in the naive recipients. The passively protected first cohort rats were immune to tumor challenge with an increased tumor dose; their splenocytes also prevented the establishment of tumor in the second cohort of naive recipient rats. This immunity transfer was accomplished without the usually required T-cell suppression in recipients.

Specificity and immunobiological properties of monoclonal antibody IMH2, established after immunization with Le(b)/Le(a) glycosphingolipid, a novel extended type 1 chain antigen.

Extended lacto-series type 1 chain antigens lacking type 2 chain core have recently been shown to comprise a new type of tumor-associated carbohydrate antigen. Examples are Le(a)/Le(a) (IV3Gal beta 1----3[Fuc alpha 1----4]Glc-NAcLc4Cer) and Le(b)/Le(a) (IV3Fuc alpha 1----2Gal beta 1----3[Fuc alpha 1----4]Glc-NAcLc4Cer) (M. R. Stroud, et al., J. Biol. Chem., 266: 8439-8446, 1991; Eur. J. Biochem., 203: 577-586, 1992). We have now established an IgG3 mouse monoclonal antibody (IMH2) after immunization of mice with Le(b)/Le(a) antigen; however, monoclonal antibody (MAb) IMH2 reacted not only with the immunogen used but also with Le(y)/Le(x) and to a lesser degree with short-chain Le(y) or Le(b) with hexasaccharide ceramide (i.e., IV2FucIII3FucnLc4Cer or IV2FucIII4FucLc4Cer). It showed a high incidence of staining and strong reactivity with carcinomas of colon, rectum, liver, pancreas, and endometrium, but no reactivity with normal colonic mucosa at various loci, and minimal reactivity with normal liver, pancreas, or uterine endometrium. On the other hand, it reacted with normal gastric mucosa, cecal mucosa, urothelium, adrenal glands, and thymus. Its expression in colorectal tumors and normal cecal tissue was independent of secretor status, whereas that in normal urothelium was dependent on secretor status. MAb IMH2 displayed strong lymphocyte-activated or complement-dependent killing of human colonic cancer Colo205 cells in vitro, and inhibition of Colo205 growth in vivo; this inhibition was comparable to that by MAb NCC-ST-421, which is directed to Le(a)/Le(a) epitope (M. Watanabe, et al., Cancer Res., 51:2199, 1991). These results indicate that a new extended type 1 chain structure, Le(b)/Le(a), is a useful tumor marker associated with carcinomas of colon, rectum, pancreas, liver, and endometrium and that MAb IMH2 has potential diagnostic or therapeutic applicability for these carcinomas.

Profiles of Lewisx-containing glycoproteins and glycolipids in sera of patients with adenocarcinoma.

Oligosaccharides with Lex determinant (Gal beta 1----4[Fuc alpha 1----3]GlcNAc) are accumulated in large quantities in various adenocarcinomas. Monoclonal antibodies recognizing mono-, di-, or trimeric Lex showed a preferential staining of specific stages of human fetal tissues and various human adenocarcinomas. Thus, these carbohydrate epitopes are typical of oncodevelopmental antigens. The present study investigated the presence of Lex epitope in sera of normal individuals and cancer patients, utilizing two high-affinity monoclonal antibodies, SH1 and SH2, directed to mono- and dimeric Lex structures, respectively. The Lex antigen in serum was eluted in the void volume fraction of a gel filtration column, determined by using monoclonal antibody SH1, and found to be carried on a glycoprotein with a molecular weight of approximately 200,000. The Lex antigen was present in the void volume fraction of the majority (85%) of sera from adenocarcinoma patients. Although the Lex epitope was also detected in a smaller proportion (33%) of normal sera, its levels were significantly lower than in cancer sera. Lex antigen was also detected in serum glycolipid fraction; however, no significant differences were observed in normal and cancer sera. A double determinant solid phase immunoassay utilizing SH2 as the capture antibody and SH1 as the detecting antibody allowed direct determination of Lex levels in sera. By the use of this direct assay, the levels of serum Lex were found to increase in association with the progression of colorectal cancer (Dukes A to D). The percentage of detectability in sera from colon cancer patients was as follows: Dukes A, 20%; Dukes B, 45%; Dukes C, 67%; and Dukes D, 74%. The levels of serum Lex were also of prognostic value in Dukes C cancer patients after surgery and during postoperative follow-up.

Presence of fucolipid antigens with mono- and dimeric X determinant (Lex) in the circulating immune complexes of patients with adenocarcinoma.

A series of fucosylated glycosphingolipids with the Lewisx (Lex) determinant (Gal beta 1----4[Fuc alpha 1----3]GlcNAc) have been shown to accumulate in human adenocarcinomas. Lex glycolipids were eluted from Protein A-silica columns over which plasma from patients with adenocarcinoma had previously been perfused. The fact that Protein A has strong affinity for IgG and IgG-immune complexes suggested that the Lex antigens isolated from Protein A eluates were complexed with IgG. Lewisx antigen eluted from Protein A columns banded in the immune complex-enriched region (below IgG) of neutral sucrose density gradients. A modified Raji cell assay and an anticomplement C1q enzyme-linked immunosorbent assay were also used for measurement of Lex antigen associated with C3- and C1q-CIC, respectively. Following affinity purification of Lex-IgG complexes and subsequent dissociation of these immune complexes, human antibodies were isolated which reacted with purified glycosphingolipids containing Lex. Levels of Lex-IgG complexes were found to be 2- to 5-fold higher in eluates of Protein A-silica columns perfused with plasma from adenocarcinoma patients compared to eluates from columns perfused with plasma from healthy individuals and patients with other cancers. These assays may prove to be of diagnostic and/or prognostic significance in adenocarcinoma.

Interactions of porphyrins and transfer RNA.

The interactions of the free base porphyrin, tetra-(4N-methylpyridyl)porphyrin and its copper(II), manganese(III) and zinc(II) complexes with brewer's yeast type V phenylalaninyl tRNA were evaluated by UV-visible spectroscopy, circular dichroism and melting temperature studies over a range of magnesium ion concentrations and ionic strengths. Scatchard analysis of absorption spectra of the porphyrins in the presence of tRNA showed the free base, copper and zinc porphyrins to have binding constants of 7.3 X 10(7), 1.7 X 10(6) and 2.3 X 10(8), respectively; the manganese(III) complex did not demonstrate changes in its electronic spectra that enable the calculation of a binding constant. The results of the spectroscopic studies indicate a mode of binding for the free base, copper(II) and zinc(II) complexes that is neither intercalative nor simply outside electrostatic. The magnitude of the binding constants and the UV-visible results support intercalation, but the analyses of the thermal denaturation studies and the circular dichroism evaluations suggest that the porphyrins are associating at a single site in a fold of the tertiary structure of the tRNA close to several crucial hydrogen bonds, perhaps in the vicinity of the P10 loop. That the manganese(III) complex does not bind in this site points to constraints on the axial thickness of a molecule that may be accommodated in this locus.

Metabolism of 3 alpha, 7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acid and 3 alpha, 7 beta-dihydroxy-7 alpha-methyl-5 beta-cholanoic acid in hamsters.

The metabolic fate of the bile acid analogs, 3 alpha, 7 alpha-dihydroxy-7 beta-methyl-5 beta-cholanoic acid and 3 alpha, 7 beta-dihydroxy-7 alpha-methyl-5 beta-cholanoic acid, was investigated and compared with that of chenodeoxycholic acid in hamsters. Both bile acid analogs were absorbed rapidly from the intestine and excreted into bile at rates similar to that of chenodeoxycholic acid. In the strain of hamster studied, the biliary bile acids were conjugated with both glycine and taurine. After continuous intravenous infusion, chenodeoxycholic acid and the analogs became the major bile acid constituents in bile. After oral administration of a single dose of these compounds, fecal analysis revealed the existence of unchanged material (25-35%) as well as considerable amounts of metabolites (65-75%). The major metabolites excreted into feces were more polar than the starting material and were tentatively identified as trihydroxy-7-methyl compounds by radioactive thin-layer chromatography. However, monohydroxy compounds were also found in the fecal extracts. These results show that chenodeoxycholic acid and ursodeoxycholic acid with a methyl group at the 7-position are more resistant to bacterial 7-dehydroxylation than the normally occurring bile acids and that a certain proportion of these analogs is hydroxylated to give the corresponding trihydroxy compound(s). In a control experiment, about 5% of administered chenodeoxycholic acid was metabolized to a trihydroxy bile acid, but most of the compound (95%) was transformed into lithocholic acid.

In vitro and in vivo induction of apoptosis by sphingosine and N, N-dimethylsphingosine in human epidermoid carcinoma KB-3-1 and its multidrug-resistant cells.

Sphingolipid breakdown products, including ceramide and sphingosine, regulate cell growth, cell differentiation, and apoptosis. We examined the effect of various agents, including sphingolipids, on apoptosis induction in human epidermoid carcinoma KB-3-1 and its multidrug-resistant (MDR) subclone KB-C2 cells which express P-glycoprotein. Adriamycin (ADM) induced apoptosis in KB-3-1 cells but not in KB-C2 MDR cells at the concentration of 50 microg/ml. On the other hand, 15 microM sphingosine or its methylated derivative N, N-dimethylsphingosine (DMS) induced apoptosis in both cell types in vitro. These results suggested that KB-C2 MDR cells were resistant to apoptosis induction by ADM but sensitive to that by sphingosine and DMS. Ceramide and sphingosine-1-phosphate, the initial metabolites of sphingosine, failed to induce apoptosis under the same experimental condition as sphingosine/DMS. The protein kinase C (PKC) inhibitors H7 and staurosporine did not induce apoptosis in either cell line, suggesting that PKC-independent signaling is involved in apoptosis induced by sphingosine and DMS, although both sphingosine and DMS have been shown to down-regulate PKC. Furthermore, DMS significantly inhibited the growth of KB-3-1 as well as KB-C2 MDR tumors in vivo, with evidence of increased apoptosis. The intracellular level of exogenously added [3H]sphingosine or [14C]DMS did not differ between the KB-3-1 parent cell line and its MDR subclone KB-C2, whereas that of [14C]ADM was reduced in KB-C2 MDR cells compared to KB-3-1 cells. These results suggest that P-glycoprotein acts as a transporter for ADM but not for sphingosine or DMS. Furthermore, DMS at the concentrations which induce apoptosis in KB-C2 cells did not affect the level of [14C]ADM. Because sphingosine and DMS induce apoptosis regardless of P-glycoprotein expression, they may provide a new strategy and a promising approach to the treatment of anticancer drug-resistant cancer.

Capillary blood versus arterial or venous blood for tacrolimus monitoring in liver transplantation.

Tacrolimus has been found to be useful in clinical solid organ transplantation. A very careful monitoring of the tacrolimus levels and dose adjustments are essential, at least in the immediate post-liver transplantation, situation. However, quite often after liver transplantation, patients have limited venous access for daily monitoring of tacrolimus levels. When the blood is sampled from a multilumen central venous catheter, used also for intravenous administration of tacrolimus, falsely elevated concentrations of tacrolimus have been observed. The present study examines the concentration of tacrolimus in capillary blood samples obtained from finger stick and compares its concentrations in simultaneously drawn samples from arterial line, peripheral venous puncture, and multilumen centrally placed venous catheter from the port used for tacrolimus infusion and the port not used for tacrolimus infusion. Ten adult post-liver transplantation recipients were studied. Whole blood concentration of tacrolimus in capillary blood was comparable to that of arterial blood, as well as to that of peripheral venous blood samples (r2 = 0.99; P = 0.72). Concentrations of tacrolimus in venous blood drawn from the port of the multilumen catheter used for intravenous tacrolimus infusion were 3-23 times higher (P = 0.0015), while the concentrations of venous blood drawn from the port not used for tacrolimus infusion were 1.7-4.5 times higher (P = 0.016), as compared with arterial, capillary, or peripheral venous whole blood concentrations.

Pharmacologic pre-conditioning and controlled reperfusion prevent ischemia-reperfusion injury after 30 minutes of hypoxia/ischemia in porcine hearts.

BACKGROUND: Hearts from non-heart-beating organ donors are not transplanted because of risk of ischemia-reperfusion injury. We tested whether pharmacologic pre-conditioning with adenosine and the Na(+)/H(+) exchanger inhibitor, cariporide, combined with controlled reperfusion, would prevent injury in porcine hearts that had sustained 30 minutes of hypoxia/ischemia in closed-chest animals. METHODS: Hearts from Yorkshire pigs (100 kg) were studied in 3 groups. Group 1 (control) hearts were surgically removed while beating. Group 2 hearts were harvested from animals made hypoxic by discontinuing mechanical ventilation for 30 minutes. Group 3 hearts were hypoxic as in Group 2, but these animals received adenosine (40 mg) and cariporide (400 mg) 10 minutes before stopping ventilation. Cardiac function in all groups was assessed ex vivo in a working heart apparatus in which pressure and flow measurements were made over 3 hours. Controlled reperfusion in Group 3 hearts used leukocyte-depleted blood perfusate containing free radical scavengers. Myocardial injury was assessed on the basis of perfusate creatine phosphokinase activity and histopathologically determined injury score. RESULTS: Groups 1 and 3 hearts could be resuscitated to perform work equivalently during the entire reperfusion period and showed positive responses to increases in pre-load and norepinephrine. Group 2 hearts could not perform work. After 3 hours, Group 2 hearts showed significantly higher creatine phosphokinase and histopathologic injury scores compared to with Groups 1 and 3, which were not significantly different from each other. CONCLUSIONS: Pharmacologic pre-conditioning and controlled reperfusion effectively protect non-beating porcine hearts from injury after 30 minutes of hypoxia/ischemia in situ.

Hyodeoxycholic acid: a new approach to gallstone prevention.

Hyodeoxycholic acid and its isomer, 6 beta-hyodeoxycholic acid, when added to a lithogenic diet prevented the formation of cholesterol gallstones and crystals in prairie dogs. This beneficial effect occurred in the presence of bile supersaturated with cholesterol. Hyodeoxycholic acid abolished the feedback inhibition of hepatic hydroxymethylglutaryl coenzyme A reductase activity, the rate-limiting enzyme of cholesterol synthesis, and prevented elevations in serum and liver cholesterol observed in animals fed a 0.4 percent cholesterol diet. The gallbladder bile of the animals fed hyodeoxycholic acid and 6 beta-hyodeoxycholic acid contained abundant liquid crystals. This suggests that these bile acids prevented the transition of cholesterol from its liquid crystalline phase to solid crystals and stones.

An experimental-computational analysis of MHV cavitation: effects of leaflet squeezing and rebound.

A combined experimental-computational study was performed to investigate the flow mechanics which could cause cavitation during the squeezing and rebounding phases of valve closure in the 29 mm mitral bileaflet Edwards-Duromedics (ED) mechanical heart valve (MHV). Leaflet closing motion was measured in vitro, and input into a computational fluid mechanics software package, CFD-ACE, to compute flow velocities and pressures in the small gap space between the occluder tip and valve housing. The possibility of cavitation inception was predicted when fluid pressures dropped below the saturated vapor pressure for blood plasma. The computational analysis indicated that cavitation is more likely to be induced during valve rebound rather than the squeezing phase of valve closure in the 29 mm ED-MHV. Also, there is a higher probability of cavitation at lower values of the gap width at the point of impact between the leaflet tip and housing. These predictions of cavitation inception are not likely to be significantly influenced by the water-hammer pressure gradient that develops during valve closure.