Opioid-induced hyperalgesia: Are thalamic T-type calcium channels treatment targets?

Opioid-induced hyperalgesia (OIH) is a state of paradoxically enhanced pain transmission, termed nociceptive sensitization, described to occur in both humans and animals after repeated administration of opioid drugs, including rapidly acting remifentanil. However, molecular mechanisms of OIH remain understudied. In this issue of the JCI, Yan Jin and colleagues provided strong evidence that hyperexcitable thalamocortical networks drive remifentanil-induced hyperalgesia in a rodent model of postsurgical pain. Furthermore, the authors specifically identified an important role of the Ca_V3.1 isoform of low-voltage-activated or T-type calcium channels (T-channels) in this process. Further experiments are needed to determine whether thalamic T channels could serve as targets for the treatment of OIH.     

Effect of treatment with LHRH analogs containing cytotoxic radicals on the binding characteristics of receptors for luteinizing-hormone-releasing hormone in MXT mouse mammary carcinoma

Binding capacities and apparent dissociation constants of receptors for luteinizing-hormone-releasing hormone (LHRH) were investigated in estrogen-independent MXT mammary cancers of untreated mice and after in vivo treatment with agonistic or antagonistic analogs of LHRH containing cytotoxic radicals: AJ-04 (agonist [d-Lys⁶]LHRH linked to methotrexate), T-98-{[d-Lys⁶]LHRH coupled to glutaryl-2-(hydroxmethyl)anthraquinone (G-HMAQ)} and T-121/B (LHRH antagonist T-147 containing two residues of G-HMAQ), which induced tumor growth inhibition. The effects were compared to LHRH agonist [d-Trp⁶]LHRH and carriers [d-Lys⁶]LHRH, LHRH antagonist T-147, as well as to methotrexate, G-HMAQ and surgical bilateral overiectomy. Analysis of the binding data revealed that in control tumors the interaction of¹²⁵I-[d-TRP⁶]LHRH was consistent with the presence of one class of saturable, specific, noncooperative, high-affinity and low-capacity binding sites. Chronic treatment of mice bearing MXT tumors with LHRH analogs AJ-04 and T-121/B carrying cytotoxic radicals, but not with T-98 produced significant down-regulation of membrane receptors for LHRH. The largest decrease in dissociation binding constant andB _max of receptors for LHRH was also found in animals treated with T-121/B. Specific, high affinity binding of¹²⁵I-labelled epidermal growth factor (EGF) was detected in the membranes from control and treated MXT tumors. Treatment with cytotoxic LHRH analogs, AJ-04, T-98 and especially with T-121/B, reduced maximal binding capacity of EGF receptors. Our results indicate that LHRH analogs carrying cytotoxic radicals retain their hormonal activity and inhibit tumor growth while inducing down-regulation of LHRH receptors. In addition, probably both components of the cytotoxic LHRH analog, peptide carriers and cytotoxic radicals, reduce the binding capacity of EGF receptors, which might be useful in the treatment of breast cancer.Abbreviations LHRH luteinizing-hormone-releasing hormone - EGF epidermal growth factor     

Comparison of cathepsin d determinations in human carcinomas by enzyme immunoassay and immunoradiometric assay

Overexpression of cathepsin D in several types of carcinoma in women appears to be associated with a poor clinical course. In this prospective investigation, cathepsin D levels in 170 specimens of normal and neoplastic human tissues were determined simultaneously by enzyme immunoassay (EIA) and immunoradiometric assay (IRMA) to allow comparisons in multicentric studies, such as cooperative clinical trials. Nonmalignant uteri and specially prepared reference powders were also evaluated. Linear regression analysis between the two assays for all specimens [EIA = 0.87(IRMA) – 3.18] demonstrated a correlation coefficient (r) of 0.99 (P <0.001). When malignancies were categorized by the tissue origin (i.e., breast, uterus, ovary, lymph node, and colon), highly significant correlations were also observed (regressions slopes ranged from 0.58 to 1.02). Intra- and interassay controls conducted for the new EIA procedure gave CV% ranging from 4.4 to 10.2, which was similar to the IRMA test for cathepsin D. The results of both assays correlated well and were highly reproducible. Either assay may be used with confidence that comparable cathepsin D values will be obtained in a wide range of tissue biopsies.     

Symmetry of the submandibular glands in humans--a postmortem study assessing the linear morphometric parameters.

BACKGROUND: The analysis of morphometric right-left symmetry of the salivary glands is important for assessing unilateral changes discovered in these organs during diagnostic imaging. STUDY DESIGN: A study was carried out on 18 adult human autopsy neck and maxillofacial specimens from both sexes (14 males, 4 females), with age range of 17 to 73 years (mean age 49.9 years). The submandibular duct was injected with contrast medium and images were made in two projection planes. RESULTS: Morphometry performed using the obtained radiographs included: (a) caliber (mean proximal, middle, and distal = 1.73 mm, 1.82 mm, and 1.77 mm), (b) length (mean = 37.2 mm); (c) genu of the submandibular duct (mean = 114 degrees ); and (d) longitudinal and transverse diameters of the gland (mean = 44.1 mm and 25.9 mm). Comparison of these morphometric parameters between the right and the left glands revealed no statistically significant differences. CONCLUSION: There is a high level of right-left symmetry in linear morphometric parameters of the submandibular gland.     

Cationic modulation of 5-HT2 and 5-HT3 receptors in rat sensory neurons: the role of K, Ca and Mg

The effects of changes in external K⁺, Ca²⁺, and Mg²⁺ concentrations on 5-HT₂- and 5-HT₃ receptor-mediated depolarizations of the resting membrane potential in rat dorsal root ganglion (DRG) cells was studied. In cells exhibiting a 5-HT₂-mediated response, 5-HT and α-methyl 5-HT depolarized the resting membrane potential (RMP) and increased the slope of the current–voltage (I/V) relationship. The equilibrium potential (E_r) for the depolarization was linearly related to the logarithm of the [K⁺]_o, indicating the depolarization resulted from a decrease in resting K⁺ conductance. In a subpopulation of large-diameter acutely dissociated DRG neurons recorded from using the whole-cell patch-clamp configuration, 5-HT produced an inward shift in the current required to hold cells at −60 mV. This inward shift in holding current was associated with a reduction in membrane conductance and reversed near E_k. This data suggests that the 5-HT₂ receptor-mediated depolarization and increase in R_in seen in intact DRG preparation is produced by blockade of an outward K⁺ leak current. Increases in [K⁺]_o reduced the increase in R_in and depolarization induced by 5-HT with 50% inhibition of the depolarization occurring at 8.3 mM of [K⁺]_o. Half-normal Ca²⁺ (1.2 mM) produced a downward shift of the 5-HT concentration–response curve, reducing the maximal response by 40%, with minimal effect on the half-maximal response. Mg²⁺ ions did not affect this 5-HT response. In cells exhibiting a 5-HT₃ receptor response, 5-HT and 2-methyl-5-HT produced depolarization with decreased R_in. The E_r for this depolarizing response (−30.2±1.8 mV) became less negative (−11.5 mV) in 10 mM [K⁺]_o with minimal effect on the amplitude of the depolarization. In Na⁺-free superfusate, the 5-HT-induced depolarization was converted to hyperpolarization. This indicated the 5-HT₃ response increased a mixed Na⁺/K⁺ conductance. Elevated Ca²⁺ or Mg²⁺ markedly reduced the 5-HT₃ response. Incubation with 3.5 mM Ca²⁺ shifted the 5-HT concentration–response curve downward and to the right, decreasing the maximal response by 49% and increasing the EC₅₀ by 10-fold. Elevated Mg²⁺ produced similar effects. In cells where both 5-HT₂- and 5-HT₃-mediated responses could be demonstrated, the elevation of K⁺ or the reduction of Ca²⁺ converted a 5-HT₂ response to a 5-HT₃ response. The above data suggest that elevation of [K⁺]_o or reduction of [Ca²⁺]_o produced by rapid firing rates of sensory neurons will favor the expression of 5-HT₃ responses over 5-HT₂ responses.     

Absolutes molekulargewicht der nativen cellulose der alge valonia

The weight-average degree of polymerisation (P _w) of unfractionated native cellulose derived from the alge valonia was found to be ca. 26 500. After fractionation using a precipitation technique a high molecular weight component of P _w≈44000 was isolated which is thought to determine the dimensions of the template present in the biosynthesis. It is approximately three times the size of that found in cotton cellulose with P _w≈14000. In conjunction with other investigations it is considered very probable, that the biosyn-thesis of the cellulose molecules takes place on a flat template leading directly to the formation of a folded chain structure. Because the diffraction patterns in the direction of the fibre axis, as expected in the case of a thermodynamic control of the chain fold length, are not observed, a “genetic” control is considered. This necessitates that the crystallisation to the cellulose I structure occurs after the detachment of the molecule from its site of formation and that it is independent of the chain fold length. It is also proposed that under this scheme an elementary fibril could exist, which consists of a single molecular band, exhibiting the commonly observed breadth of 35Å and a chain fold length of 10⁴ and 3·10⁴ Å in the case of cotton and alge valonia, respectively.     

Normal AV Node Function in Patients with Sinus Node Dysfunction After Cardiac Transplantation

A bstract Postoperative atrioventricular nodal (AVN) function was compared in 55 patients with normal and 50 patients with impaired sinus node (SN) function after cardiac transplantation (corrected SN recovery time > 520 msec or sinus arrest ± escape rhythm). Fifty-two patients had fixed atrial pacing at cycle lengths between 600 and 430 msec, and 53 patients at cycle lengths from 600 to 300 msec between postoperative weeks 1 to 3. Relative (stimulus-R interval; AVNRRP) and effective AVN refractory period (AVNERP) were determined in 53 patients at a cycle length of 500 msec. Only one of 105 recipients had high degree AVN conduction disturbance characterized by a Wenckebach phenomenon at cycle length < 630 msec in the first postoperative week. Three patients with normal and two patients with impaired SN function had Wenckebach cycle lengths > 430 msec while the Wenckebach cycle lengths were < 430 msec in the remainder (p = NS). Resting PQ interval (146 ± 18 vs 162 ± 32; p = 0.09), Wenckebach cycle length (350 ± 53 vs 362 ± 50 msec), AVNRRP (356 ± 38 vs 367 ± 37 msec), and AVNERP (217 ± 48 vs 244 ± 49 msec) did not differ significantly between patients with normal and impaired SN function. AVN conduction did not deteriorate during 318 ± 130 days of follow-up (PQ at follow-up 154 ± 17 and 158 ± 22 msec, patients with normal and impaired SN function, respectively). One DDD pacemaker was placed for AVN conduction disturbance while 22 pacemakers were implanted for SN deficiency. In conclusion, AVN conduction is usually unimpaired in patients with SN dysfunction after cardiac transplantation. These patients are good candidates for single chamber atrial pacing.     

Von einer importierten Katze übertragene, durch M. canis hervorgerufene Mikrosporie bei Menschen und Hund

Es wurden die häufigsten Kulturanlagen der Dermatophyten des Einzugsgebietes der Belgrader Dermatologischen Klinik ausgewertet. Am häufigsten wurden bei Landbewoh-nern die klassischen anthropophilen Dermatophyten und animale "microides"- und "megasporon"-Pilzarten isoliert. Bei Stadtbewohnern dominierten in den positiven Kulturanlagen Tr. mentagrophytes var. interdigitale, Ep. floccosum und Tr. rubrum. Ver-einzelte Isolate von M. Audouini und Tr. ferrugineum gehören den migrierenden Dermatophyten, die aus dem Norden bzw. Süden des Landes in diesem Gebiet zeitweilig importiert werden.
M. canis als importierter Dermatophyt hat einstweilen für unser Gebiet keine epidemiologische Bedeutung. Die Isolierung desselben verbreitert jedoch das Spektrum der Dermatophyten und weist auf die Möglichkeit des Erscheinens dieses animalen Mikrosporums auch bei uns hin.