Heteroplasmic pathogenic m.12315G>A variant in MT-TL2 presenting with MELAS syndrome and depletion of nitric oxide donors.

The MT-TL2 m.12315G>A pathogenic variant has previously been reported in five individuals with mild clinical phenotypes. Herein we report the case of a 5-year-old child with heteroplasmy for this variant who developed neurological regression and stroke-like episodes similar to those observed in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Biochemical evaluation revealed depletion of arginine on plasma amino acid analysis and low z-scores for citrulline on untargeted plasma metabolomics analysis. These findings suggested that decreased availability of nitric oxide may have contributed to the stroke-like episodes. The use of intravenous arginine during stroke-like episodes and daily enteral L-citrulline supplementation normalized her biochemical values of arginine and citrulline. Untargeted plasma metabolomics showed the absence of nicotinamide and 1-methylnicotinamide, and plasma total glutathione levels were low; thus, nicotinamide riboside and N-acetylcysteine therapies were initiated. This report expands the phenotype associated with the rare mitochondrial variant MT-TL2 m.12315G>A to include neurological regression and a MELAS-like phenotype. Individuals with this variant should undergo in-depth biochemical analysis to include untargeted plasma metabolomics, plasma amino acids, and glutathione levels to help guide a targeted approach to treatment.

Integrative Medicine: Manual Therapy.

Manual therapy, or manipulative therapy, is performed primarily by osteopathic physicians, chiropractors, and physical therapists to relieve pain and improve function. As safe prescribing of opioids has become a concern and nondrug therapies for pain management are used more widely, manual therapy has become an attractive treatment option for many patients. A variety of techniques are used, including myofascial release, strain-counterstrain, muscle energy, high velocity/low amplitude, Still, and others. The most common conditions for which patients seek manual therapies are back pain, neck pain, and extremity problems. These therapies also are used to manage many other conditions. Studies show that, in general, manual therapies may improve pain and function in the short and moderate term in patients with acute and chronic back pain, neck pain, rotator cuff conditions, and temporomandibular joint disorders. These therapies also are used in patients with sciatica, migraine, carpal tunnel syndrome, pregnancy-related pelvic girdle pain, and infantile colic. Manual therapies may result in improvements in these conditions, but there is no high-quality research to confirm their benefits. Many studies show benefits that are similar to those of other commonly used therapies, or that are not superior to the benefits shown with sham manipulation.

Integrative Medicine: Acupuncture.

Acupuncture is used to manage pain and a variety of medical and psychological conditions. It modulates nociceptive areas of the brain, affects neuropeptide and purinergic signaling, and stimulates production of opioid neuropeptides. There are many types of acupuncture, including traditional, dry needling, laser, auricular, scalp, Japanese, and Korean. There is evidence that traditional acupuncture is effective in the management of many conditions, with strong evidence of benefit for chronic back pain and osteoarthritis-related knee pain. In the United States, the conditions most commonly managed with acupuncture are low back pain, depression, anxiety, headache, and arthritis. There are no absolute contraindications. Relative contraindications include frailty and febrile illness. Acupuncture should not be used in areas of skin infection or breakdown. Acupuncture typically is avoided during the first trimester of pregnancy. Reports of serious adverse effects are rare but include pneumothorax, infection, organ or tissue injuries, and seizures. Serious adverse effects of electroacupuncture (eg, skin burns, pacemaker or implantable cardioverter-defibrillator dysfunction) are limited to case reports. Thirty-three states in the United States consider acupuncture to be within the scope of practice of physicians. Other states require specific acupuncture training. Medicare provides coverage for acupuncture for management of chronic low back pain.

Integrative Medicine: Herbal Supplements.

Various herbal medicines have been used around the world for more than 5,000 years. Herbal medicines, or herbal supplements, are defined as any products originating from plants and used to preserve or recover health. In the United States, the popularity of herbal supplements has increased in the last several decades. Many physicians do not ask patients about herbal supplement use, and one-third of patients do not inform their physician about supplement use. However, physicians should ask, because although many supplements are considered low risk and safe, some have significant risks of adverse effects. For example, St John's wort (Hypericum perforatum) can have significant drug interactions with prescription or over-the-counter drugs. The effectiveness of herbal supplements in the management of specific conditions varies. For some conditions, there is robust clinical data supporting the use of specific herbal supplements, but for other conditions there is poor or insufficient data. The content and safety of herbal supplements are the purview of the Food and Drug Administration (FDA). However, the FDA primarily responds to after-the-fact reports of postmarketing safety concerns. When an herbal supplement-related adverse effect is suspected, patients or physicians should report it to the FDA via the MedWatch reporting system.

Integrative Medicine: Cannabis and Cannabis-Related Drugs.

Cannabis is a genus of flowering herbs in the Cannabaceae family. Federal law defines dried plant material preparations of the subspecies Cannabis sativa as marijuana. The term cannabis refers to all products derived from Cannabis plants. The active compounds in cannabis are cannabinoids, which include delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the psychoactive component, whereas CBD has no psychoactive effects. There are three Food and Drug Administration (FDA)-approved cannabis-related drugs. Dronabinol and nabilone (Cesamet) are approved for chemotherapy-induced nausea and vomiting; cannabidiol (Epidiolex) is approved for two pediatric epilepsy syndromes. FDA-approved cannabis-related drugs, marijuana, and cannabis formulations have been studied for the management of other conditions and symptoms (eg, cachexia, chemotherapy-induced nausea and vomiting, chronic pain, muscle spasticity) and have shown varying effectiveness. CBD formulations have been shown to be effective for certain forms of epilepsy. However, marijuana, cannabis-containing products, and cannabis-derived products in general are not approved by the FDA for any indication. Adverse effects include impaired executive function, cognition, and driving. Physicians can recommend use of marijuana under medical marijuana laws but cannot prescribe it, as it is classified as a Schedule I controlled substance. Laws regulating use of marijuana and cannabis products vary among states.

Successful management of Mycobacterium haemophilum lower extremity cutaneous infection in a matched-unrelated donor stem cell transplant recipient.

Nontuberculous mycobacterial infections can often occur in individuals with adequate immune function. Such infections typically have cutaneous involvement and are caused by rapidly growing mycobacterium. Other nontuberculous mycobacteria species, like Mycobacterium haemophilum, almost always present as opportunistic infections occurring in severely immunocompromised hosts. Here, we present a complicated and protracted course of diagnosing M. haemophilum lower extremity cutaneous infection in a matched-unrelated donor stem cell transplant recipient.

Treating Painful Diabetic Peripheral Neuropathy: An Update.

Painful diabetic peripheral neuropathy occurs in approximately 25% of patients with diabetes mellitus who are treated in the office setting and significantly affects quality of life. It typically causes burning pain, paresthesias, and numbness in a stocking-glove pattern that progresses proximally from the feet and hands. Clinicians should carefully consider the patient's goals and functional status and potential adverse effects of medication when choosing a treatment for painful diabetic peripheral neuropathy. Pregabalin and duloxetine are the only medications approved by the U.S. Food and Drug Administration for treating this disorder. Based on current practice guidelines, these medications, with gabapentin and amitriptyline, should be considered for the initial treatment. Second-line therapy includes opioid-like medications (tramadol and tapentadol), venlafaxine, desvenlafaxine, and topical agents (lidocaine patches and capsaicin cream). Isosorbide dinitrate spray and transcutaneous electrical nerve stimulation may provide relief in some patients and can be considered at any point during therapy. Opioids and selective serotonin reuptake inhibitors are optional third-line medications. Acupuncture, traditional Chinese medicine, alpha lipoic acid, acetyl-l-carnitine, primrose oil, and electromagnetic field application lack high-quality evidence to support their use.

Comparison of the basal cell-specific markers, 34betaE12 and p63, in the diagnosis of prostate cancer.

The basal cell-specific cytokeratin antibody (34betaE12) is widely used to aid in the diagnosis of cancer in challenging prostate needle biopsies (NBX) and transurethral resections of the prostate (TURP). Because prostate carcinoma (PCa) lacks basal cells, the absence of basal cell as determined by 34betaE12 can aid in the confirmation of a histologically suspicious lesion. However, false-negative staining occurs because of patchy cytoplasmic staining, making a definitive diagnosis difficult. A recently identified basal cell marker p63, a p53 homologue, stains basal cell nuclei but not secretory cells. The aim of this study is to determine if the p63 antibody offers any clinically useful advantage over 34betaE12 in the diagnosis of challenging atypical prostate lesions. Ninety-four cases, comprised of 25 consecutive prostate NBX and 2 TURP with an atypical suspicious focus, 55 NBX cases of histologically unequivocal PCa and 12 TURP specimen removed for benign prostate hyperplasia, were stained with the monoclonal antibodies 34betaE12 and 4A4 anti-p63. Basal cell staining intensity, percentage basal cell-positive glands in benign, malignant, and atypical foci, and number of benign glands not staining were evaluated for 34betaE12 and p63 stains. A total of 67 prostate NBX cases, including one TURP, were diagnosed with PCa, 1 atypical small acinar proliferation, 10 benign, and 4 cases excluded because of lost tissue on step sections. None of the 67 PCa NBX cases demonstrated 34betaE12 or p63 immunoreactivity (100% specific). Whereas 57 of 108 (53%) prostate NBX cores from 78 cases demonstrated a similar percentage of basal cell staining for both antibodies, 45 of 108 (41%) NBX cores demonstrated a higher percentage of p63 basal cell staining in benign glands. Only 6 of 108 NBX (6%) cores had a higher percentage of basal cell staining with 34betaE12 (Wilcoxon signed rank test, p <0.0001). Lack of basal cell staining in more than two benign glands occurred in 25 of 108 (23%) and 10 of 108 (9%) prostate NBX cores stained with 34betaE12 and p63, respectively. In the vast majority of atypical cases, both 34betaE12 and p63 staining differences were not clinically significant, except in 2 of 27 (7%) cases p63 offered diagnostic utility beyond the 34betaE12 immunostain. p63 in these cases demonstrated discontinuous but strong staining in atypical glands and adjacent benign glands, whereas 34betaE12 failed to stain optimally in this critical area. For 12 TURP cases the mean percentage basal cell positivity in benign glands was 75% and 95% for 34betaE12 and p63, respectively (p = 0.006). Lack of basal cell staining in more than two glands occurred in 12 of 12 (100%) and 2 of 12 (17%) TURP specimens stained with 34betaE12 and p63, respectively (p <0.0001). In summary, 34betaE12 and p63 are highly specific for basal cells and therefore are negative in areas of PCa. p63 is more sensitive than 34betaE12 in staining benign basal cells, particularly for TURP specimens, offering slight advantage over 34betaE12 in diagnostically challenging cases. p63 may be used as an alternative to 34betaE12 stain for difficult prostate lesions.

Current applications of electrotherapeutics in collagen healing.

Electrical current flow appears to be integral to the healing of collagen containing tissue, i.e., bone, cartilage, ligaments, tendons and skin. Accordingly, it is reasonable to hypothesize that externally applied electrical fields should be able to enhance healing, especially in conditions that have resisted more standard treatments. Nevertheless, applications of electrotherapeutics is challenging because the precise mechanism of action is unknown and, accordingly, there is an almost unlimited combination of stimulation parameters (e.g., type of waveform, voltage, current, phase, frequency, etc.) that can be applied to a treatment site. Presently, of the three major types of electrical stimulation, i.e., direct, and capacitive and inductive coupling, there is a growing trend toward utilization of the latter because of its efficacy and greater margin of safety. Although the mechanisms of action for enhanced healing of all three types remain elusive there is increasing evidence that electrical stimulation exerts its influence via effects at the cellular and/or molecular levels within the tissue. Utilization of electrotherapeutics has been most prevalent in bony injuries resistant to healing, but applications to severe lesions of skin and ligaments, and even to degenerative joint disease seems promising as cartilage has been shown to be more responsive than bone to applied electrical energy. We conclude that there is a clear trend toward greater orthopedic utilization of inductive stimulation and that, despite the lack of definitive guidelines relating specific parameters with specific conditions, electrotherapeutics appears to be a safe and often effective treatment for collagen containing tissues in many cases in which more standard therapies have failed.