Endogenous tissue engineering: PTH therapy for skeletal repair

Based on its proven anabolic effects on bone in osteoporosis patients, recombinant parathyroid hormone (PTH_1-34) has been evaluated as a potential therapy for skeletal repair. In animals, the effect of PTH_1-34 has been investigated in various skeletal repair models such as fractures, allografting, spinal arthrodesis and distraction osteogenesis. These studies have demonstrated that intermittent PTH_1-34 treatment enhances and accelerates the skeletal repair process via a number of mechanisms, which include effects on mesenchymal stem cells, angiogenesis, chondrogenesis, bone formation and resorption. Furthermore, PTH_1-34 has been shown to enhance bone repair in challenged animal models of aging, inflammatory arthritis and glucocorticoid-induced bone loss. This pre-clinical success has led to off-label clinical use and a number of case reports documenting PTH_1-34 treatment of delayed-unions and non-unions have been published. Although a recently completed phase 2 clinical trial of PTH_1-34 treatment of patients with radius fracture has failed to achieve its primary outcome, largely because of effective healing in the placebo group, several secondary outcomes are statistically significant, highlighting important issues concerning the appropriate patient population for PTH_1-34 therapy in skeletal repair. Here, we review our current knowledge of the effects of PTH_1-34 therapy for bone healing, enumerate several critical unresolved issues (e.g., appropriate dosing regimen and indications) and discuss the long-term potential of this drug as an adjuvant for endogenous tissue engineering.     

Existence of Sites for Anions and Divalent Cations in the Solubilized γ-Aminobutyric Acid/Benzodiazepine Receptor Complex

This study evaluated the ability of gamma-aminobutyric acid (GABA), baclofen, monovalent anions, divalent cations, and various combinations thereof to protect solubilized benzodiazepine (BZ) receptors of types 1 and 2, when contained together on the complex, against heat inactivation. Neither anions, cations, nor GABA alone provided significant protection of solubilized BZ receptors against heat, but inclusion of monovalent anions or divalent cations together with 500 microM GABA did afford protection. Monovalent anions combined with GABA (500 microM) provided 50% to full protection. Divalent cations, such as CaCl2 (2.5 mM) or MgCl2 (2.5 mM) in the presence of GABA (500 microM) yielded 45% and 24% protection, respectively. Other divalent cations tested (Zn2+, Hg2+, Co2+, and Ni2+) were poor protectors, even when combined with GABA. Monovalent anions (200 mM NaCl) and divalent cations (5 mM CaCl2) when tested together provided no protection. Similarly, baclofen (the GABA-B agonist) provided no protection, either alone or together with anions or divalent cations. These results indicate that the independent but interacting recognition sites of GABA, BZ, anions, and divalent cations, previously detected in the membrane-bound state, are retained in the solubilized state.     

Peripheral-type benzodiazepine receptors in human cerebral cortex, kidney, and colon.

The specific binding of [3H]PK 11195 and [3H]Ro 5-4864 to human cerebral cortex, kidney, and colon membranes was studied in order to determine whether peripheral type benzodiazepine receptors (PBR) characteristics located in human tissues are similar to those located in calf or rat tissues. While [3H]PK 11195 (0.05-10 nM, final concentration) bound with high affinity (KD about 2 nM) to human cerebral cortex, kidney, and colon membranes, yielding maximal numbers of binding sites of 255 +/- 23, 1908 +/- 28, and 1633 +/- 98 fmol/mg protein, respectively, the specific binding of [3H]Ro 5-4864 (1.25-40 nM, final concentration), was barely detectable (nonspecific binding about 90% of the total binding). Furthermore, unlabeled PK 11195 was two orders of magnitude more potent than unlabeled Ro 5-4864 in displacing [3H]PK 11195 specific binding from human cerebral cortex and kidney membranes. These results indicate that PBR binding characteristics located in human tissues are similar (but not identical) to those located in calf tissues, but not to those located in rat tissues.     

Emphysematous pyelonephritis

A case of emphysematous pyelonephritis with perirenal gas is presented. This patient underwent vigorous medical treatment followed by nephrectomy and survived. This condition has a high mortality and should be distinguished from less severe infections where gas is confined to the collecting system. This case and others previously reported suggest that treatment should initially be medical, followed by early surgical intervention consisting of either drainage or nephrectomy depending upon the degree of renal involvement.     

Camel myoglobin

1. Crystalline myoglobin was prepared from camel heart muscle. 2. A method was developed for the isolation of myoglobin that employs molecular-sieve chromatography. 3. Analytical chromatography of the camel myoglobin on a molecular-sieve column and on two types of ion-exchange columns gave in each case a single elution band, which accounted for better than 98% recovery and showed that the product was free from haemoglobin. 4. The iron content on a dry weight basis was 0.308%. This value corresponds to a molecular weight of 18100. 5. The spectra of acidic ferrimyoglobin, basic ferrimyoglobin and ferrimyoglobin cyanide were measured. 6. The pK(a) of the dissociation of the haem-bound water molecule in acidic ferrimyoglobin was 8.53 at 25 degrees . 7. Conclusions are drawn about the charge on the surface of the camel ferrimyoglobin molecule as compared with horse and sperm-whale ferrimyoglobins.     

An Ustilago maydis Mutant Partially Blocked in P45014DM Activity Is Hypersensitive to Azole Fungicides

An Ustilago maydis ergosterol biosynthesis mutant (A14) which is partially blocked in sterol 14alpha-demethylase (P45014DM) activity is described. This mutant accumulated the abnormal 14alpha-methyl sterols, eburicol, 14alpha-methylfecosterol, and obtusifoliol, along with significant amounts of ergosterol. Although the A14 mutant grew nearly as well as the wild type, it was impaired in cell extension growth, which indicated a dysfunction in apical cell wall synthesis. The mutant was also found to be hypersensitive to the azole fungicides penconazole and tebuconazole.     

Renal function in patients receiving long-term lithium therapy.

Renal function was assessed in 42 stable outpatients who had been taking lithium for an average of 4 1/2 years. Impaired ability to concentrate the urine was found in 61% of the 41 patients who provided a urine sample for an osmolality measurement, and a moderate reduction in creatinine clearance was present in 12% of the entire group; 1 patient showed both defects. Urine microscopy revealed an excess of cells in 40%. It is suggested that lithium therapy produces a self-limiting lesion of the distal nephron that does not usually progress to chronic renal failure. The lesion is not dangerous, except that it may predispose to acute neurotoxic effects in the event of intercurrent illness or dehydration.