The reported clinical utility of taurine in ischemic disorders may reflect a down-regulation of neutrophil activation and adhesion

The first publications regarding clinical use of taurine were Italian reports claiming therapeutic efficacy in angina, intermittent claudication and symptomatic cerebral arteriosclerosis. A down-regulation of neutrophil activation and endothelial adhesion might plausibly account for these observations. Endothelial platelet-activating factor (PAF) is a crucial stimulus to neutrophil adhesion and activation, whereas endothelial nitric oxide (NO) suppresses PAF production and acts in various other ways to antagonize binding and activation of neutrophils. Hypochlorous acid (HOCl), a neutrophil product which avidly oxidizes many sulfhydryl-dependent proteins, can be expected to inhibit NO synthase while up-regulating PAF generation; thus, a vicious circle can be postulated whereby HOCl released by marginating neutrophils acts on capillary or venular endothelium to promote further neutrophil adhesion and activation. Taurine is the natural detoxicant of HOCl, and thus has the potential to intervene in this vicious circle, promoting a less adhesive endothelium and restraining excessive neutrophil activation. Agents which inhibit the action of PAF on neutrophils, such as ginkgolides and pentoxifylline, have documented utility in ischemic disorders and presumably would complement the efficacy of taurine in this regard. Fish oil, which inhibits endothelial expression of various adhesion factors and probably PAF as well, and which suppresses neutrophil leukotriene production, may likewise be useful in ischemia. These agents may additionally constitute a non-toxic strategy for treating inflammatory disorders in which activated neutrophils play a prominent pathogenic role. Double-blind studies to confirm the efficacy of taurine in symptomatic chronic ischemia are needed.     

Niacinamide therapy for osteoarthritis--does it inhibit nitric oxide synthase induction by interleukin 1 in chondrocytes?

Fifty years ago, Kaufman reported that high-dose niacinamide was beneficial in osteoarthritis (OA) and rheumatoid arthritis. A recent double-blind study confirms the efficacy of niacinamide in OA. It may be feasible to interpret this finding in the context of evidence that synovium-generated interleukin-1 (IL-1), by inducing nitric oxide (NO) synthase and thereby inhibiting chondrocyte synthesis of aggrecan and type II collagen, is crucial to the pathogenesis of OA. Niacinamide and other inhibitors of ADP-ribosylation have been shown to suppress cytokine-mediated induction of NO synthase in a number of types of cells; it is therefore reasonable to speculate that niacinamide will have a comparable effect in IL-1-exposed chondrocytes, blunting the anti-anabolic impact of IL-1. The chondroprotective antibiotic doxycycline may have a similar mechanism of action. Other nutrients reported to be useful in OA may likewise intervene in the activity or synthesis of IL-1. Supplemental glucosamine can be expected to stimulate synovial synthesis of hyaluronic acid; hyaluronic acid suppresses the anti-catabolic effect of IL-1 in chondrocyte cell cultures, and has documented therapeutic efficacy when injected intra-articularly. S-adenosylmethionine (SAM), another proven therapy for OA, upregulates the proteoglycan synthesis of chondrocytes, perhaps because it functions physiologically as a signal of sulfur availability. IL-1 is likely to decrease SAM levels in chondrocytes; supplemental SAM may compensate for this deficit. Adequate selenium nutrition may down-regulate cytokine signaling, and ample intakes of fish oil can be expected to decrease synovial IL-1 production; these nutrients should receive further evaluation in OA. These considerations suggest that non-toxic nutritional regimens, by intervening at multiple points in the signal transduction pathways that promote the synthesis and mediate the activity of IL-1, may provide a substantially superior alternative to NSAIDs (merely palliative and often dangerously toxic) in the treatment and perhaps prevention of OA.     

Down-regulation of microglial activation may represent a practical strategy for combating neurodegenerative disorders

Chronic neurodegenerative disorders are characterized by activation of microglia in the affected neural pathways. Peroxynitrite, prostanoids, and cytokines generated by these microglia can potentiate the excitotoxicity that contributes to neuronal death and dysfunction in these disorders--both by direct effects on neurons, and by impairing the capacity of astrocytes to sequester and metabolize glutamate. This suggests a vicious cycle in which the death of neurons leads to microglial activation, which in turn potentiates neuronal damage. If this model is correct, measures which down-regulate microglial activation may have a favorable effect on the induction and progression of neurodegenerative disease, independent of the particular trigger or target involved in a given disorder. Consistent with this possibility, the antibiotic minocycline, which inhibits microglial activation, shows broad utility in rodent models of neurodegeneration. Other agents which may have potential in this regard include PPARgamma agonists, genistein, vitamin D, COX-2 inhibitors, statins (and possibly policosanol), caffeine, cannabinoids, and sesamin; some of these agents could also be expected to be directly protective to neurons threatened with excitotoxicity. To achieve optimal clinical outcomes, regimens which down-regulate microglial activation could be used in conjunction with complementary measures which address other aspects of excitotoxicity.     

The pathophysiology of stress fractures

Stress fractures can occur in any active individual, from the weekend warrior to the elite athlete. As these injuries occur, it is important to understand how bones respond to the stresses placed on them. The understanding of potential intrinsic and extrinsic causes is important in treatment of these injuries. The proper identification and prevention of these stress injuries allows for athletes to return to activity expeditiously.     

Prospective,double‐blind,randomized clinical trial comparing an ERAS pathway with ketorolac and pregabalin versus standard of care plus placebo during live donor nephrectomy for kidney transplant

Opioid exposure is a concern after live donation for kidney transplant. We theorized that an enhanced recovery after surgery pathway (ERAS) using pregabalin preoperatively to desensitize nerves followed by the nonsteroidal anti‐inflammatory drug ketorolac, during and after surgery, can control pain, thus requiring less perioperative narcotics. The aim of this study was to determine if the use of a nonopioid analgesic ERAS protocol for donor nephrectomies could decrease the use of narcotics without an increase in complications compared with standard of care (SOC). This is a single‐center, prospective, double‐blind, randomized clinical trial involving a total of 62 patients undergoing nephrectomy for live donor kidney transplant. Length of hospital stay (LOS) was significantly reduced by 10% in the ERAS group versus the SOC‐plus‐placebo group. Morphine dose equivalents were significantly reduced by 40% in the study group versus the SOC‐plus‐placebo group. The use of this nonopioid analgesic ERAS pathway for donor nephrectomies decreased the use of narcotics without an increase in complications compared with SOC. There was significantly reduced LOS and less narcotic use in the study group versus the SOC‐plus‐placebo group. (ClinicalTrials.gov registration number: NCT03669081).     

Incisional or excisional neck-node biopsy before definitive radiotherapy, alone or followed by neck dissection

An analysis of 508 patients (660 heminecks) with head and neck squamous cell carcinoma and clinically positive neck nodes who were treated with radiotherapy alone to the primary lesion (with or without a neck dissection) was conducted to determine if open neck-node biopsy before definitive treatment adversely affected the probability of control of neck disease, the risk of distant metastasis, or the cause-specific survival rate. The prognostic factors analyzed included biopsy status of the neck, N stage, neck treatment, node mobility, node location, T stage, primary site, and control of disease above the clavicles. Sixty-six patients who had undergone an open neck-node biopsy before definitive radiotherapy were compared with a control group of 442 patients who did not undergo a neck-node biopsy; no detrimental effect of the biopsy on neck control, distant metastasis, or cause-specific survival was demonstrated. We conclude that the potential adverse effect of violating the neck before definitive treatment cannot be demonstrated if radiotherapy is the next step in the patient's management.     

Altered folate and vitamin B12 metabolism in families with spina bifida offspring

Folic acid intake reduces the risk of neural tube defects (NTDs). Although the 677C-->T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene is a risk factor for NTDs, it only partly explains the elevated homocysteine levels in mothers of children with NTDs. We measured vitamin B12, folate and homocysteine in patients with spina bifida (SB), their parents, and in controls, to investigate which other enzymes of homocysteine metabolism might be defective. Because homozygosity for the 677C-->T mutation causes decreased plasma folate and increased red-cell folate (RCF) and plasma homocysteine levels, we excluded individuals homozygous for that mutation. The remaining SB patients and their parents still had lowered plasma folate and elevated total homocysteine levels, and a small subset had decreased vitamin B12 levels. Red-cell folate was the same in all groups, suggesting that dietary folate intake and its uptake was normal. Risk of SB was increased at the 25th percentile of plasma folate and at the 75th percentile of homocysteine values in SB patients and their parents, and at the 5th and 25th percentiles of vitamin B12 in mothers with SB- affected offspring. This underlines the functional importance of homocysteine remethylation to methionine. There was no correlation between vitamin B12 and homocysteine or RCF. In combination with the lowered plasma folate (80-90% 5-methyltetrahydrofolate), our data do not support a major involvement of methionine synthase in the aetiology of SB. Our data rather favour the involvement of genetic variation at loci coding for the formation of 5-methyltetrahydrofolate, such as MTHFR, methylenetetrahydrofolate dehydrogenase or serine hydroxymethyltransferase.