WHAT'S WHERE AND WHY AT A VASCULAR MYOENDOTHELIAL MICRODOMAIN SIGNALLING COMPLEX

• 1 Modulation of vascular cell calcium is critical for the control of vascular tone, blood flow and pressure.
• 2 Specialized microdomain signalling sites associated with calcium modulation are present in vascular smooth muscle cells, where spatially localized channels and calcium store receptors interact functionally. Anatomical studies suggest that such sites are also present in endothelial cells.
• 3 The characteristics of these sites near heterocellular myoendothelial gap junctions (MEGJs) are described, focusing on rat mesenteric artery. The MEGJs enable current and small molecule transfer to coordinate arterial function and are thus critical for endothelium‐derived hyperpolarization, regulation of smooth muscle cell diameter in response to contractile stimuli and vasomotor conduction over distance.
• 4 Although MEGJs occur on endothelial cell projections within internal elastic lamina (IEL) holes, not all IEL holes have MEGJ‐related projections (approximately 0–50% of such holes have MEGJ‐related projections, with variations occurring within and between vessels, species, strains and disease).
• 5 In rat mesenteric, saphenous and caudal cerebellar artery and hamster cheek pouch arteriole, but not rat middle cerebral artery or cremaster arteriole, intermediate conductance calcium‐activated potassium channels (IK_Ca) localize to endothelial cell projections.
• 6 Rat mesenteric artery MEGJ connexins and IK_Ca are in close spatial association with endothelial cell inositol 1,4,5‐trisphosphate receptors and endoplasmic reticulum.
• 7 Data suggest a relationship between spatially associated endothelial cell ion channels and calcium stores in modulation of calcium release and action. Differences in spatial relationships between ion channels and calcium stores in different vessels reflect heterogeneity in vasomotor function, representing a selective target for the control of endothelial and vascular function.

     

Convergence of nociceptive information in the forebrain of female rats: reproductive organ response variations with stage of estrus

Neurons in the preoptic area (POA) of the hypothalamus and the bed nucleus of stria terminalis (BST) play an important role in the neuroendocrine control of the reproductive cycle, mating behaviors and nociception. Single unit extracellular recordings were performed in the POA and BST region of 20 urethane anesthetized female rats during either the proestrus (elevated levels of estrogen/progesterone) or metestrus (low circulating hormones) stage of the estrous cycle. A total of 118 neurons in the POA and 65 neurons in the BST responded to the search stimuli, bilateral electrical stimulation of the viscerocutaneous branch of the pelvic nerve and/or sensory branch of the pudendal nerve (i.e., dorsal nerve of clitoris). Most of the neurons responding to the electrical search stimuli received a high degree of somatovisceral convergence, including inputs from the abdominal branches of the vagus, cervix, vagina, colon and skin territories on the perineum and trunk. Mean neuronal response thresholds for vaginal and cervical stimulation but not colon distention were significantly higher for animals tested during proestrus. Also, there was a shift in POA and BST neuronal responsiveness towards more inhibition and less excitation during proestrus for a variety of somatovisceral inputs. These data demonstrate that the changes in hormonal status affect the properties of POA and BST neurons, which likely relates not only to the functional importance of these inputs for reproductive behaviors but also for nociceptive processing as well.     

Quantitative analysis of in vitro compatibility of binary and ternary mixtures of nitroimidazole and macrolides in combination with omeprazole using a calorimetric technique

In the present study, in vitro interactions between nitroimidazoles, macrolides and omeprazole in binary and ternary mixtures were examined by measuring their enthalpy of solution (delta(sol)H) using a calorimetric technique. A comparison of the enthalpy of solution of the pure drugs with those of binary and ternary mixtures at pH 2 and 6 was made to indicate the magnitude of interaction between them. The delta(sol)H for all the nitroimidazoles is endothermic at pH 2 and 6 but both the macrolides show exothermic behavior, whereas the enthalpy of solution of omeprazole changes from -40.52 to 4.35 kJmol(-1) as the pH changes from 2 to 6. The results have been quantified by determining the excess enthalpy of solution for both binary and ternary systems. The small deviations from ideality for all the binary systems are attributed to various non-bonding interactions between different functional groups on both the drug molecules. The results suggest compatibility of drug pairs in their binary mixtures. However, ternary mixtures show somewhat larger interactions. The magnitude of interaction enthalpy of a ternary mixture comprising tinidazole, clarithromycin and omeprazoles which are available as a marketed kitshas been calculated to be significant, suggesting that the three drugs cannot be co-formulated.     

Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma

BACKGROUND: Growth factor overexpression, including epidermal growth factor receptor (EGFR) expression, is common in hepatocellular cancers. Erlotinib is a receptor tyrosine kinase inhibitor with specificity for EGFR. The primary objective of this study was to determine the proportion of hepatocellular carcinoma (HCC) patients treated with erlotinib who were alive and progression-free (PFS) at 16 weeks of continuous treatment. METHODS: Patients with unresectable HCC, no prior systemic therapy, performance status (PS) of 0, 1, or 2, and Childs-Pugh (CP) cirrhosis A or B received oral erlotinib 150 mg daily for 28-day cycles. Tumor response was assessed every 2 cycles by using Response Evaluation Criteria in Solid Tumors (RECIST; National Cancer Institute Cancer Therapy Evaluation Program, Bethesda, Md) criteria. Patients accrued to either "low" or "high" EGFR expression cohorts; each cohort had stopping rules applied when there was a lack of efficacy. RESULTS: Forty HCC patients were enrolled. Median age was 64 years (range, 33-83 years), sex distribution was 32 males and 8 females, performance scores were 40% PS 0, 55% PS 1, Childs-Pugh distribution was 75% A and 20% B. There were no complete or partial responses; however, 17 of 40 patients achieved stable disease at 16 weeks of continuous therapy. The PFS at 16 weeks was 43%, and the median overall survival (OS) was 43 weeks (10.75 months). No patients required dose reductions of erlotinib. No correlation between EGFR expression and outcome was found. CONCLUSIONS: Results of this study indicated that single-agent erlotinib is well tolerated and has modest disease-control benefit in HCC, manifested as modestly prolonged PFS and OS when compared with historical controls.     

Gall Bladder Carcinoma Presenting with Spinal Metastasis: A Rare Phenomenon

Skeletal metastasis as a primary presentation of gall bladder carcinoma is rare. A 50-year-old lady presented with neck pain and weakness in her right upper limb of 3 months duration. Clinical and imaging work-up suggested locally advanced gall bladder carcinoma with metastasis to cervical vertebra and sternum. Only one case till date has been reported where the patient presented with neurological symptoms due to pathological fracture secondary to metastasis from an occult gall bladder carcinoma. Although rare, an occult gall bladder cancer may present with neurological symptoms due to pathological fracture of spine secondary to metastasis. We present a brief review of literature of patients who presented with skeletal metastases in clinically silent gall bladder malignancy. Palliative care issues in advanced gall bladder carcinoma have also been discussed.     

Low-grade immature teratomas with peritoneal gliomatosis; a case report

Immature teratomas with peritoneal gliomatosis are rare. Eight cases have been registered by the Dutch Ovarian Tumor Committee and one patient, presented in this paper, was treated recently. The follow-up in these cases indicates a good prognosis, even in grade 2 teratomas. Peritoneal implants do not influence adversely the prognosis when they are composed of mature glial tissue. A conservative approach seems to be justified.     

Radiation therapy in the management of medically inoperable carcinoma of the lung: results and implications for future treatment strategies.

Surgery is the treatment of choice for resectable non-small cell lung carcinoma. For patients who are medically unable to tolerate a surgical resection or who refuse surgery, radiation therapy is an acceptable alternative. We reviewed the records of 152 patients with medically inoperable non-small cell lung carcinoma treated at our institution between 1982 and 1990. Patients with metastatic disease, mediastinal lymph node involvement or unresectable tumors were excluded. The actuarial overall survival at 2 and 5 years was 40% and 10%, respectively. The disease-free survival at 2 and 5 years was 31% and 15%. The disease-free survival for patients with T1 tumors was 55% at 2 years, versus 20 and 25% for T2 and T3 lesions, respectively (p = .0006). Increasing tumor dose was also associated with increasing disease-free survival (p = .0143). Overall, 66% percent of the patients were considered to have failed. Of these, 70% showed a component of local failure and 45% failed distantly. Patients with T1 tumors experienced a lower probability of failing locally or distantly than did patients with T2 or T3 tumors. A reduced risk of local and distant failure was seen for patients treated to doses of greater than 65 Gray, especially for T1 tumors. We conclude that radical radiation therapy is an effective treatment for small tumors when treated to doses of 65 Gray or more. Since local failure is the prominent pattern of relapse in patients with large tumors, new therapeutic strategies should be considered for this patient group.     

Changes in transthoracic electrical impedance at high altitude.

Mean transthoracic electrical impedance (impedance) which is inversely related to intrathoracic extravascular fluid volume was measured in 121 normal healthy volunteers at sea-level and at 3658 metres altitude. Fifty (group A) reached the high altitude location after an hour's journey in a pressurised aircraft. Twenty-five (group D) underwent slow road ascent including acclimatisation en route. Thirty permanent residents (group B) and 16 temporary residents at high altitude (group C) were also studied. Serial studies in the 30 subjects of group A who developed symptoms of high altidue sickness showed a significant decrease of impedance up to the fourth day of exposure to high altitude which later returned to normal. The 4 volunteers who developed severe symptoms showed the largest drop in impedance. A case of acute pulmonary oedema developing at 4300 metres showed an impedance value of 24-1 ohms on admission. After effective treatment the impedance increased by 11-9 to 36-0 ohms. Twenty asymptomatic subjects of group A and 25 of group D showed a small average increase in impedance values at high altitude. These obstructions suggest that measurement of transthoracic electrical impedance may be a valuable means of detecting incipient high altitude pulmonary oedema.     

The forked flap repair for hypospadias

Context:

Despite the abundance of techniques for the repair of Hypospadias, its problems still persist and a satisfactory design to correct the penile curvature with the formation of neourethra from the native urethral tissue or genital or extragenital tissues, with minimal postoperative complications has yet to evolve.

Aim:

Persisting with such an endeavor, a new technique for the repair of distal and midpenile hypospadias is described.

Materials and Methods:

The study has been done in 70 cases over the past 11 years. The “Forked-Flap” repair is a single stage method for the repair of such Hypospadias with chordee. It takes advantage of the rich vascular communication at the corona and capitalizes on the established reliability of the meatal based flip–flap. The repair achieves straightening of the curvature of the penis by complete excision of chordee tissue from the ventral surface of the penis beneath the urethral plate. The urethra is reconstructed using the native plate with forked flap extensions and genital tissue relying on the concept of meatal based flaps. Water proofing by dartos tissue and reinforcement by Nesbit''s prepucial tissue transfer completes the one stage procedure.

Statistical Analysis:

An analysis of 70 cases of this single stage technique of repair of penile hypospadias with chordee, operated at 3 to 5 years of age over the past 11 years is presented.

Results and Conclusion:

The Forked Flap gives comparable and replicable results; except for a urethrocutaneous fistula rate of 4% no other complications were observed.KEY WORDS: Chordee, fistula, forked flap, hypospadias, urethral plate