In 1992, our esteemed colleagues Alan Breier, Orlando Davis, Robert Buchanan, Samuel J. Listwak, Courtney Holmes, David Pickar, and David S. Goldstein published a seminal scientific paper titled "Effects of Alprazolam on Pituitary-Adrenal and Catecholaminergic Responses to Metabolic Stress in Humans." In it, they described with high accuracy the effects of benzodiazepines on stress-induced activation of the three classic "stress" systems: Pituitary-adrenal, adrenal medullary, and sympathoneural systems. The results provided an answer to a question that is still being asked today: Why is alprazolam so much more effective than all other benzodiazepines for certain anxiety-related conditions, especially panic attacks? The colleagues found the answer to that question, but although the work was impeccable, their findings never made it into medical textbooks. What Breier et al. found was this: Alprazolam is able to attenuate 2DG-induced activation of the HPA axis and adrenomedullary activity, as evidenced by attenuated responses of plasma levels of ACTH and epinephrine, respectively, without clinically affecting other important responses of two indices of sympathoneural activity. For the treatment of patients whose adrenal glands are working in a highly dysfunctional or centrally dysregulated manner due to rare diseases such as NTBI induced H63D syndrome, alprazolam is still the first drug of choice - despite its dependence potential - to protect the organism of the affected person from dangerous adrenaline excesses that are way more dangerous than any well-monitored use of alprazolam.

Since H63D syndrome was first described, the authors of this paper systematically investigated for the first time to what extent the adrenal glands, as an integral part of the HPA and SAM axes, are also affected by damage caused by non-transferrin bound iron (NTBI), a hallmark of H63D syndrome. Due to the rarity of the H63D syndrome, the representatives of a number of institutions that regularly deal with the topic in the context of their clinical and research activities have come together for this purpose. Thus, a small but significant amount of patient data could be collected worldwide, analyzed and evaluated, with surprisingly clear pathological results. A secondary aspect is that after reviewing the currently available literature, the team of authors came to the conclusion that the issue of HPA and SAM axes dysfunctions and adrenal synthesis activity seems to be also more frequent in other iron metabolic disorders than it is addressed to in everyday’s clinical practice. The result of this work is a warning call to closely monitor the catecholamine balance, the synthesis and control of all "stress hormones", the condition of the adrenal glands as well as other axis structures very early in the course of the H63D syndrome, in order to make unnecessary organ damages at least a little less likely, if not to prevent it to a large extent if detected early.

Since the market launch of alprazolam (in many countries under the brand name Xanax), this highly potent benzodiazepine has had a disastrous public reputation. Even in media, entertainment and pop culture, its very powerful effects have made it emblematic of a sinister psychodrug that drags its users into an abyss of dependence and suffering. Indeed, the substance has certain specific properties (mood elevating, extremely fast acting, very short half-life, effects on adrenaline), but at its core it is a benzodiazepine like any other. How Xanax came to be demonized is therefore an important question to be discussed. On the other hand, the substance alprazolam possesses a unique property that is hardly known even among experts to this day and can be life-saving for people whose body's own adrenaline synthesis and regulation is disturbed by certain (often hereditary, auto-immune, or toxic) rare diseases. For these patients, there is virtually no other medication available than alprazolam, which quickly, specifically and highly effectively inhibits pathological adrenaline surges, for example due to disorders of the SAM axis, effectively at the site of adrenaline (epinephrine) synthesis by up to 50%. Logically, this also gives rise to the legendary reputation that alprazolam is more effective than any other benzodiazepine, especially in patients with panic disorders. This paper, a source-supported opinion piece, is intended to remind the worldwide community of medical professionals that alprazolam is a legitimate, and often the only available, treatment option for abnormal adrenaline balance involving the adrenal gland and/or the SAM axis. Demonizing alprazolam in a clinically well regulated setting is therefore immoral and detrimental to the patients health and compliance.

Update 2.7We report the case of a patient who suffers from hypotransferrinemia due to a genetic defect, subsequently suffers organ damage due to non-transferrin bound iron (NTBI) and develops a paradoxical reaction of glucose metabolism as a result of treatment with corticosteroids. To our knowledge, this is the first description of such an effect in the medical literature. The mechanism and further course of this phenomenon are currently still in the dark. Due to its peculiarity, we therefore publish only the clinical key data for the time being. We reported earlier about the same patient’s change in his narcolepsy symptoms.

We report the case of a patient who suffers from hypotransferrinemia due to a genetic defect, subsequently suffers organ damage due to non-transferrin bound iron (NTBI) and develops a paradoxical reaction of glucose metabolism as a result of treatment with corticosteroids. To our knowledge, this is the first description of such an effect in the medical literature. The mechanism and further course of this phenomenon are currently still in the dark. Due to its peculiarity, we therefore publish only the clinical key data for the time being 

After the short-term administration of 20mg/d prednisolone (orally) in a previously non-steroid-treated patient with iron storage disease, the steroid, which is omnipresent in clinical practice, led to paradoxical foudroyant symptoms, but above all to a reduction of 80% in the extreme narcoleptic symptomatology, not however in the cataplectic component. Masked primary adrenal insufficiency was revealed. An improvement in narcoleptic symptoms of about 50% was also maintained under oral hydrocortisone-only substitution therapy.

A minority of neurologists is convinced that the disease "dementia praecox" first described by Emil Kraepelin in 1899 is still valid and its annexation by psychoanalysis and later by psychiatry has caused severe damage. The psychoanalytic extremist Eugen Bleuler had successfully annexed all conceivable mental conditions for Freud's couch therapy and had withdrawn them from medical research by his own postulates, which could never be proven. A recent further study now supports Kraepelin's once discarded thesis in a new way. This gives rise to a commentary by physicians on the clinical front.

H63D syndrome, now clinically known as Oslo syndrome (synonymous), is considered a very rare disorder that is difficult to recognize due to its multifaceted nature. Even with homozygous mutation of the HFE gene H63D and the simultaneous presence of the typical clinical symptoms, few clinicians dare to care for affected patients. This is inexplicable, because Oslo syndrome (H63D syndrome) looked at on the meta-level is nothing more than Wilson disease caused by NTBI iron.

Evidence-based medicine has shown for many years that homozygous mutations of the HFE gene H63D are by no means negligible. Not only can it cause, usually after a second hit, rather mild classical hemochromatosis, but it can also cause numerous other disorders of iron metabolism, such as hypotransferrinemia, changes in binding capacity, and others. In addition, it may lead-among other symptoms-to damages of the heart and the substantia nigra via a causal relationship that remains to be investigated, most likely via a cascade dysfunction in iron metabolism. The clinical facts are compelling. Any physician who dismisses mutations of the HFE gene H63D as clinically irrelevant risks the health and life of his patient. Therefore all main researcher working on H63D Syndrome decided to raise awareness for the "iron brother" of Morbus Wilson by renaming H63D Syndrome.

Evidence-based medicine has shown for many years that homozygous mutations of the HFE gene H63D are by no means negligible. Not only can it cause, usually after a second hit, rather mild classical hemochromatosis, but it can also cause numerous other disorders of iron metabolism, such as hypotransferrinemia, changes in binding capacity, and others. In addition, it may lead - among other symptoms - to damages of the heart and the substantia nigra via a causal relationship that remains to be investigated, most likely via a cascade dysfunction in iron metabolism. The clinical facts are compelling. Any physician who dismisses mutations of the HFE gene H63D as clinically irrelevant risks the health and life of his patient. We report two patients with an HFE H63D mutation who were treated almost too decades too late because of outdated expertise.

Skin cancer, especially malignant melanoma, can vary greatly in appearance and usually develops very quickly. Therefore, the ABCDE rule (also known as the ABCD rule in some countries) was propagated many years ago to help medical laymen to recognize for themselves when it is time to see a dermatologist. But how effective is this rule? Our previous work clearly demonstrates that another self-monitoring protocol has a higher sensitivity and better results than the outdated ABCDE rule: the C-Rapid-H-Plus Protocol. Based on this, a simple algorithm was developed which appeared to give quite promising results. Now we can present a completely new algorithm that has proven to be more reliable than dermatoscopy in predicting the need for excisional biopsy in a collective of 421 patients. The CRHP Advanced Risk Calculator, also based on the C-Rapid-H-Plus protocol, is of great value for both, in-person and telemedicine settings.

Skin cancer, especially malignant melanoma, can vary greatly in appearance and usually develops very quickly. Therefore, the ABCDE rule (also known as the ABCD rule in some countries) was propagated many years ago to help medical laymen to recognize for themselves when it is time to see a dermatologist. But how effective is this rule? Our previous work clearly demonstrates that another self-monitoring protocol has a higher sensitivity and better results than the outdated ABCDE rule: the C-Rapid-H-Plus Protocol which has also become an important tool in tele-dermatology.