Low-molecular-weight heparins in thrombosis and cancer: emerging links

Heparin as well as low-molecular-weight heparins (LMWHs) have polypharmacological actions at various levels. Earlier studies focused on the plasma anti-Xa and anti-IIa pharmacodynamics (PD) for the different LMWHs. Other important PD parameters for heparin and LMWHs might explain the diverse clinical impacts of this class of agents in thrombosis and beyond: the release of the vascular tissue factor pathway inhibitor (TFPI), inhibition of key matrix-degrading enzymes, and other mechanisms. There is much evidence for the key role of LMWHs in hypercoagulation in thrombosis and cancer, angiogenesis, and inflammatory disorders. Many cancer patients reportedly have a hypercoaguable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Studies have demonstrated that unfractionated heparin (UFH) or its low molecular weight fractions interfere with various processes involved in tumor growth and metastasis. Clinical trials have suggested a clinically relevant and improved efficacy of LMWHs, as compared to UFH, on the survival of cancer patients with deep vein thrombosis. Our laboratory has demonstrated a significant role for LMWHs and for LMWH-releasable TFPI on the regulation of angiogenesis, tumor growth, and tumor metastasis; we have also seen potent inhibition of matrix-degrading enzymes by LMWHs but not by TFPI. The antiangiogenesis effect of LMWHs or non-anticoagulant LMWH derivatives was shown to be reversed by anti-TFPI. Thus, modulation of tissue factor/VIIa noncoagulant activities by LMWH-releasable TFPI and the inhibitory effects on matrix-degrading enzymes beside the anticoagulant efficacy have provided an expanded clinical utility for LMWHs in angiogenesis-associated disorders, including human tumor growth and metastasis.     

Synergy of medial and lateral hamstrings at three positions of tibial rotation during maximum isometric knee flexion

Rotation of the knee has been used to isolate the strength of the medial and lateral hamstrings during manual testing of the knee flexors. The purpose of this study was to determine if medial and lateral rotation of the knee during manual knee flexor strength testing increased the electromyographic activity of the respective hamstrings. Twenty-three women between 22 and 36 years old with no history of lower extremity injury or disease participated in the study. Indwelling fine wire electrodes were used to record EMG activity of the medial (semitendinosus and semimembranosus) and lateral (long and short heads of the biceps femoris) hamstring muscles during maximally resisted knee flexion with neutral, medial, and lateral rotation of the knee. Repeated measures analysis of variance with post hoc Bonferroni adjustments were used to compare EMG activity across the three tests. EMG activity increased significantly for the target hamstrings during ipsilateral rotation (P<0.05). The semitendinosus had a mean activity of 109% Max. during medial rotation as opposed to 95% Max. during lateral rotation. The semimembranosus averaged 107 and 89% Max. in medial and lateral rotation respectively. Conversely, both the long and short head of the biceps muscle showed significantly higher activity (P<0.05) during lateral compared to medial rotation (110 and 108% compared to 93 and 97%, respectively). Even though the differences are statistically significant they ranged from 2 to 13% only of maximum activity, the clinical importance of this small change in EMG activity is questionable.     

Colosigmoid junction: a study of its functional activity with identification of a physiologic sphincter and involvement in reflex actions.

The colosigmoid junction (CSJ) marks the termination of the descending colon (DC) and the beginning of the sigmoid colon (SC); it is a fixed area in the retroperitoneum. At this site where two functionally different areas meet, we hypothesized the presence at the CSJ of a physiologic sphincter that regulates the passage of gut contents from the DC to the SC. This hypothesis was investigated for this communication. Eight subjects (mean age 36.6 +/- 4.7 SD years, 6 women) were studied during surgical repair of incisional hernia or laparotomy. The pressure responses of the CSJ to individual distension of the DC and SC were recorded. A balloon-ended tube was introduced per annum to lie in the DC or SC, and the pressure in the DC, CSJ, and SC was measured by saline-perfused catheters. To study whether the CSJ response to individual DC or SC distension was a direct or reflex action, the test was repeated in six of eight patients after separate anesthetization of the DC, CSJ, and SC. The CSJ had a higher pressure than that of the DC or SC; the high-pressure zone measured a mean of 2.1 +/- 0.9 cm. High-volume DC distension effected a significant DC pressure rise (p <.001) and a CSJ pressure decline (p <.05), which lasted a mean of 7.2 +/- 1.2 s. In contrast, the CSJ responded to big volume SC distension by significant pressure elevation (p <.001) which was also momentary. Small volume distension of the DC or SC effected no significant CSJ pressure response (p >.05). The CSJ pressure did not respond to distension of the anesthetized DC or SC. Likewise, the anesthetized CSJ did not react to DC or SC distension. When the test was repeated using saline instead of xylocaine, the CSJ pressure response was similar to that without saline injection. The CSJ is a high pressure zone with a measurable length. It reacts to DC or SC balloon distension by dilatation or narrowing, respectively. These findings presumably denote the existence of a "physiologic sphincter" at the CSJ, which appears to regulate the passage of colonic contents to the SC. We postulate that the CSJ pressure response to DC or SC distension is reflex and mediated through the "colosigmoid reflexes." The role of the colosigmoid sphincter and reflexes in colonic motility disorders remains to be investigated.     

Effect of straining on perineal muscles and their role in perineal support: identification of the straining-perineal reflex

OBJECTIVE: The functional activity of the superficial (STPM) and deep (DTPM) transverse perineal muscles is poorly addressed in the literature. We investigated the hypothesis that these muscles act to support the perineum during increased intraabdominal pressure (IAP). METHODS: 46 healthy volunteers (mean age 30.4 +/- 1.2 y, 20 nulliparous women) were studied. The IAP was recorded by a manometric catheter introduced into the rectum. The response of the perineal muscles to straining (sudden by coughing and slow by Valsalva's maneuver) was registered by a needle electrode inserted into the STPM and DTPM separately. The response was recorded again after individual anesthetization of the perineal muscles and rectum using Xylocaine. The test was repeated using saline instead of Xylocaine and was performed on both sides. RESULTS: Straining (sudden or slow sustained) effected increase of the rectal pressure and the motor unit action potentials of both perineal muscles. The higher rectal pressure was increased by straining, the higher the motor unit action potentials increased MUAPs. The latency showed a gradual decrease upon incremental rectal pressure elevation. The perineal muscles did not respond to straining after individual anesthetization of the rectum and perineal muscles, but did respond to saline administration. The response was similar from muscles on both sides. CONCLUSIONS: Perineal muscle contraction on straining postulates a reflex relationship that we call the "straining-perineal reflex." We suggest that this reflex, which results in perineal muscle contraction, supports the perineum against the increased IAP induced by straining and the tendency of the perineum to descend. The results warrant further study of the role of the straining-perineal reflex in the genesis of perineal functional disorders.     

Medical management of nocturnal symptoms of gastro-oesophageal reflux disease in the elderly

Elderly patients with nocturnal symptoms of gastro-oesophageal reflux disease (GORD) usually experience a more aggressive and complicated disease course compared with younger patients, resulting in impaired quality of life. The severity of disease and possible complications should be evaluated with upper endoscopy once the diagnosis is suspected. Elderly patients with nocturnal symptoms of GORD and evidence of endoscopic complications (oesophagitis, Barrett's oesophagus, etc.) and those with severe endoscopically negative reflux disease (ENRD) should be treated with proton pump inhibitors. Histamine H(2) receptor antagonists are suitable for mild-to-moderate ENRD. Antacids and lifestyle modifications may be incorporated into the management as adjuncts to more potent and durable therapeutic agents. Effective treatment of nocturnal GORD symptoms in the elderly will result in relief of symptoms, healing of oesophagitis and improved quality of life, and should be maintained indefinitely to prevent relapses of the disease.     

Recent advances in the diagnosis and treatment of deep vein thrombosis: a regional consensus

Considerable progress has been made in the understanding of the risk factors for venous thromboembolism (VTE). The clinical applications of molecular techniques have allowed identification of important inherited, yet not uncommon, risk factors for VTE, such as mutations that cause Factor V Leiden and prothrombin G20210A. However, advances in our understanding have raised several questions regarding the need for, and duration of anticoagulation. At the end of the treatment period, low molecular weight heparins have become the drugs of choice and standard-of-care for VTE. In this review, cost effective diagnostic approaches for patients with suspected deep vein thrombosis, and recommended treatment options using evidence-based approaches, are described.     

Recurrent pleural effusion complicating liver cirrhosis

BACKGROUND: Pleural effusion (PE) is a rare complication of advanced liver cirrhosis, which may lead to an operation when uncontrolled. The purpose of this study was to evaluate the modality of the occurrence of pleural effusion and to describe its surgical management. METHODS: We studied 21 patients who were referred to the department of thoracic surgery because of massive and recurrent PE caused by liver cirrhosis. The PE was a transudate in 16 patients and an exudate in 5. Talc pleurodesis was attempted in all patients. The patients were divided into two groups. Video assisted thoracoscopy was performed in 13 patients in whom the clinical condition permitted general anesthesia; the pleural cavity was entirely explored before pleurodesis (group 1). Chest tube drainage alone was performed in 8 patients who were unable to undergo general anesthesia; talc pleurodesis was performed through the chest tube in these patients (group 2). RESULTS: In group 1 the PE was right-sided in 8 patients, left-sided in 3, and bilateral in 2. Diaphragmatic defects were observed in 2 patients, and a fluid leak oozing from the diaphragm was observed in 1 patient. Ten patients were considered cured and were without recurrence. Two patients underwent late recurrence before dying from their liver cirrhosis. Only 1 patient had an early recurrence that was cured by complementary talc slurry. In group 2 all patients presented with a right PE; of these, 3 patients died from septic shock caused by pleural infection. Three patients underwent early recurrence but were cured after repeat talc slurry. One patient had a midterm recurrence. One patient had an early recurrence treated by intrahepatic porto-systemic shunt with partial improvement. CONCLUSIONS: Passage of ascites through diaphragmatic defects appears to be the main cause of PE complicating cirrhosis. Patients may benefit from talc pleurodesis. Video assisted thoracoscopy pleurodesis is the technique of choice with consistent results. Repeated talc injection through the drain may prove useful for patients in poor clinical status.     

Effect of perineal compression on vesical motor activity

OBJECTIVE: It has been reported that digital pressure on the perineum inhibits bladder contraction; however, the mechanism is not fully understood. We investigated the hypothesis that this mechanism may be reflex in nature. MATERIAL AND METHODS: A total of 21 healthy volunteers (13 males; mean age 42.3 +/- 11.8 years) were studied. A barostat system consisting of a balloon-ended catheter connected to a strain gauge and air-injection system was used to assess vesical tone. The catheter was introduced into the urinary bladder and the balloon was inflated with 150 ml of air. Digital pressure was exerted on the perineum and the vesical tone was simultaneously assessed by recording the balloon volume variations, expressed as the percentage change from the baseline volume. The test was repeated after separate anesthetization of the perineum and bladder with xylocaine and after using normal saline instead of xylocaine. RESULTS: Digital pressure on the perineum effected a significant decrease in vesical tone, which ranged from 42% to 84% (mean 67.5% +/- 12.5%) of the baseline value. The mean latency was 18.6 +/- 2.6 ms. There was no significant difference between men and women in terms of vesical tone response to perineal pressure. Digital perineal pressure applied 20 min after individual anesthetization of the perineum and bladder produced no significant changes in vesical tone. The response returned after the anesthetic effect had waned. The vesical tone response following saline administration was similar to that before administration. CONCLUSIONS: Vesical tone decrease in response to digital pressure on the perineum suggests a reflex relationship which was absent on individual anesthetization of the two possible arms of the reflex arc: the perineal skin and urinary bladder. We call this relationship the "perineovesical reflex". This reflex may have the potential to be used as an investigative tool in the diagnosis of vesical motor disorders.     

Structurally related immunological effects of triterpenoid saponins

The influence of the triterpenoid saponins 1-10 has been investigated on murine spleenocytes in the lymphocyte transformation test and on murine macrophages in an phagocytosis assay. The lymphocyte transformation test and the phagocytosis assay showed that the tested compounds have no stimulating effect. However, a significant inhibition of lymphocyte proliferation by the triterpenoid saponins 2, 6 and 10 was demonstrated.     

A simple strategy for breakpoint fragment determination in chronic myeloid leukemia

Molecular characterization is considered a part of the routine work-up of chronic myeloid leukemia (CML) cases. Southern blot analysis using the universal BCR (UBCR) probe on BglII-digested DNA samples is the most commonly used technique, while employing the human 3' bcr probe (PR-1) is usually considered a complementary tool. In this study, we tried to develop a simple and economic strategy for molecular characterization of CML using the 3' probe as it has been shown to be the one capable of locating the breakpoint site. Seventy-eight cases of CML were studied. Molecular analysis was performed using the Southern blot technique. DNA was digested with Bam HI, BglII, EcoRI, and XbaI. Hybridization was performed using the human 3' bcr (PR-1) probe. BamHI and BglII could differentiate fragment 1 (F1) showing rearrangement (R) with Bam HI and germline configuration (G) with BglII; F2/3 showing R with both, and F4 showing R with BamHI and G with BglII. F2/3 cases were further divided by HindIII enzyme into F2 showing (G) and F3 showing (R). Fragment 0 showed G with both, but R with EcoRI and/or XbaI, while 3' deletion gave G with all four enzymes. Our results showed a relative incidence of 6.4% for F0, 20.5% for F1, 32.1% for F2, 19.2% for F3, 15.4% for F4, and 6.4% for 3' deletion. Sixty cases were evaluated clinically and hematologically and were followed up for disease evolution and survival. They included 32 cases in early chronic phase, 24 in late chronic phase, two in acceleration, and two in blastic crisis. No significant correlation was encountered between the breakpoint site and any of the clinical and hematological data except those patients with 3' deletion who showed a very short survival. The study emphasizes Southern blotting as the method of choice for molecular characterization of CML and offers a simple and economic strategy for diagnosis and determination of breakpoint fragment.