The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist

Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT₁) receptors in rabbit aorta and human recombinant AT₁ receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'₂ = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [¹²⁵I]AII binding to rabbit aortic membranes (AT, receptors) and [¹²⁵I][Sar¹, Ile⁸]AII binding to human recombinant AT₁ receptors in a concentration-dependent manner with IC₅₀ values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [¹²⁵I)AII binding to bovine cerebellum membranes (ÀT₂ receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT₁ receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT₁ selective angiotensin receptor antagonist which exerts a competitive antagonism in the [¹²⁵I]AII binding assay and insurmountable AT₁ receptor antagonism in the functional study.     

Day case stapled haemorrhoidopexy for prolapsing haemorrhoids

OBJECTIVE: Conventional surgical management of prolapsing haemorrhoids is by excisional haemorrhoidectomy. Postoperative pain has restricted the application of such procedures in the day case setting. These operations remain associated with a period of restricted activity. The use of circular stapling devices as an alternative to the excisional approach in the management of haemorrhoids has been described. This study reports our experience of stapled haemorrhoidopexy as a day case procedure. METHODS: Patients with third or fourth degree haemorrhoids were eligible for the procedure. Patients were considered suitable candidates for day case surgery based on conventional parameters. Symptoms were assessed using a previously validated symptom severity rating score. Stapled haemorrhoidopexy was carried out using a circular stapling device. Pain scores were obtained prior to discharge. Patients were admitted if pain was uncontrolled despite oral analgesia. Symptoms were re-scored at six-week follow-up. RESULTS: Over a 70-month period 168 consecutive stapled haemorrhoidopexies were performed or directly supervised by one consultant colorectal surgeon. One hundred and ten (65%) patients were considered appropriate candidates for day case surgery by conventional criteria. Ninety-six (87.3%) patients successfully underwent stapled haemorrhoidopexy on a day case basis. Fourteen (12.7%) patients required admission on the day of surgery (5 for early postoperative bleeding, 4 for pain necessitating continuing opiate analgesia, two for urinary retention and three for surgery performed late in the day). Six (5%) patients were re-admitted postoperatively; four for pain relief and two because of urinary retention. Of the day case patients, 91 (82.7%) and 56 (50.9%) had been seen for 6 week and 6 month review, respectively, at the time of analysis. Symptom scores were 6 (pre-operatively) vs 0 (postoperatively) (P < 0.01). 76/91 (83.5%) patients reviewed at 6/52 were asymptomatic. CONCLUSION: Stapled haemorrhoidopexy is a safe and effective procedure that can be carried out on selected patients on a day case basis. Complications are of a similar nature to excisional haemorrhoidectomy.     

A Chinese adolescent girl with Fechtner-like syndrome

We describe a 15-y-old girl with Fechtner-like syndrome, who is the first Chinese reported to have this rare syndrome. She presented with left homonymous hemianopia and neuroimaging revealed haemorrhage in both parietal and occipital lobes. Peripheral blood smear showed macrothrombocytopenia and intracytoplasmic inclusion bodies inside leucocytes. Thrombocytopenia and proteinuria responded to intravenous immunoglobulin and pulsed methylprednisolone. This case illustrates that life-threatening haemorrhage can occur in patients with Fechtner syndrome. Although there was no effective treatment reported in the literature, high dose steroid and immunoglobulin seemed to be useful in our patient. Our patient also had nephritic-nephrotic syndrome with renal insufficiency, which is unusual in adolescent female patients.     

Solid and papillary epithelial neoplasms of the pancreas: CT findings

Five female patients and one male patient with solid and papillary epithelial neoplasms of the pancreas were examined with computed tomography (CT). The mean age of the patients was 27 years (range, 13-46 years). All cases showed well-encapsulated, round or lobulated masses consisting of both cystic and solid areas. Cystic portions showed CT numbers that suggested hemorrhagic necrosis. There were no internal septations within the masses. In three tumors located in the head of the pancreas, dilatation of the biliary tree was absent or minimal, although the masses were large. Two tumors contained calcifications. One tumor demonstrated metastatic deposits in liver and lymph nodes. Metastatic masses appeared similar to the primary pancreatic mass. Solid and papillary neoplasm of the pancreas should be the primary diagnostic consideration when characteristic CT findings are detected in a young female patient.     

In vitro cytolysis of primitive neuroectodermal tumors of the posterior fossa (medulloblastoma) by lymphokine-activated killer cells

Short-term stimulation of nonantigen-primed peripheral blood mononuclear leukocytes with interleukin-2 generates a population of oncolytic effectors designated "lymphokine-activated killer" (LAK) cells. These LAK cells express potent lytic activity against a wide spectrum of fresh or cultured autochthonous (patient's own) and allogeneic (unrelated) tumors, yet specifically spare normal tissues. In this study, cells derived from primitive neuroectodermal tumors of the posterior fossa (PNET-PF) were examined for their sensitivity to LAK cytolysis utilizing an in vitro 4-hour chromium-51-release assay. Five early-passage cell lines, derived from primary PNET-PF, demonstrated significant sensitivity to LAK cell cytolysis. Lysis was equally effective in culture medium and cerebrospinal fluid. Three freshly excised PNET-PF exhibited similar susceptibility to lysis by autochthonous LAK cells. Greatly increased expansion of LAK cell cultures could be achieved by short-term stimulation with monoclonal anti-CD3 antibodies in addition to interleukin-2 activation. These findings constitute the preliminary in vitro foundations for potential intrathecal adoptive immunotherapy of PNET-PF with LAK cells.     

Intrarater Reliability of Functional Performance Tests for Subjects With Patellofemoral Pain Syndrome

OBJECTIVE: Patellofemoral pain syndrome (PFPS) is a common clinical entity seen by the sports medicine specialist. The ultimate goal of rehabilitation is to return the patient to the highest functional level in the most efficient manner. Therefore, it is necessary to assess the progress of patients with PFPS using reliable functional performance tests. Our purpose was to evaluate the intrarater reliability of 5 functional performance tests in patients with PFPS. DESIGN AND SETTING: We used a test-retest reliability design in a clinic setting. SUBJECTS: Two groups of subjects were studied: those with PFPS (n = 29) and those with no known knee condition (n = 11). The PFPS group included 19 women and 10 men with a mean age of 27.6 +/- 5.3 years, height of 169.80 +/- 10.5 cm, and weight of 69.59 +/- 15.8 kg. The normal group included 7 women and 4 men with a mean age of 30.3 +/- 5.2 years, height of 169.55 +/- 9.9 cm, and weight 69.42 +/- 14.6 kg. MEASUREMENTS: The reliability of 5 functional performance tests (anteromedial lunge, step-down, single-leg press, bilateral squat, balance and reach) was assessed in 15 subjects with PFPS. Secondly, the relationship of the 5 functional tests to pain was assessed in 29 PFPS subjects using Pearson product moment correlations. The limb symmetry index (LSI) was calculated in the 29 PFPS subjects and compared with the group of 11 normal subjects. RESULTS: The 5 functional tests proved to have fair to high intrarater reliability. Intrarater reliability coefficients (ICC 3,1) ranged from.79 to.94. For the PFPS subjects, a statistical difference existed between limbs for the anteromedial lunge, step-down, single-leg press, and balance and reach. All functional tests correlated significantly with pain except for the bilateral squat; values ranged from.39 to.73. The average LSI for the PFPS group was 85%, while the average LSI for the normal subjects was 97%. CONCLUSIONS: The 5 functional tests proved to have good intrarater reliability and were related to changes in pain. Future research is needed to examine interrater reliability, validity, and sensitivity of these clinical tests.