Hippuric acid has long been used as an indicator of toluene exposure; however, there appears to be some doubt about its validity. There is significant endogenous hippuric acid production by humans; which shows inter- and intra-individual variation influenced by factors such as diet, medical treatment, alcohol consumption, etc. This suggests that hippuric acid may be an unreliable indicator of toluene exposure. It has been suggested that urinary hippuric acid, the traditional marker of toluene exposure is simply not sensitive enough to separate the exposed from the non-exposed. This has led to the investigation of other metabolites as markers for toluene exposure.

Urinary "o"-cresol may be more reliable for the biomonitoring of toluene exposure because, unlike hippuric acid, "o"-cresol is not found at detectable levels in unexposed subjects. o-Cresol may be a less sensitive marker of toluene exposure than hippuric acid. o-Cresol excretion may be an unreliable method for measuring toluene exposure because o-cresol makes up <1% of total toluene elimination.

Benzylmercapturic acid, a minor metabolite of toluene, is produced from benzaldehyde. In more recent years, studies have suggested the use of urinary benzylmercapturic acid as the best marker for toluene exposure, because: it is not detected in non-exposed subjects; it is more sensitive than hippuric acid at low concentrations; it is not affected by eating or drinking; it can detect toluene exposure down to approximately 15 ppm; and it shows a better quantitative relationship with toluene than hippuric acid or "o"-cresol.

Serious adverse behavioural effects are often associated with chronic occupational exposure and toluene abuse related to the deliberate inhalation of solvents. Long-term toluene exposure is often associated with effects such as: psychoorganic syndrome; visual evoked potential (VEP) abnormality; toxic polyneuropathy, cerebellar, cognitive, and pyramidal dysfunctions; optic atrophy; and brain lesions.

The neurotoxic effects of long-term use (in particular repeated withdrawals) of toluene may cause postural tremors by upregulating GABA receptors within the cerebellar cortex. Treatment with GABA agonists such as benzodiazepines provide some relief from toluene-induced tremor and ataxia. An alternative to drug treatment is vim thalamotomy. The tremors associated with toluene misuse do not seem to be a transient symptom, but an irreversible and progressive symptom which continues after solvent abuse has been discontinued.

There is some evidence that low-level toluene exposure may cause disruption in the differentiation of astrocyte precursor cells. This does not appear to be a major hazard to adults; however, exposure of pregnant women to toluene during critical stages of fetal development could cause serious disruption to neuronal development.

6-Pyruvoyltetrahydropterin synthase deficiency is an autosomal recessive disorder that causes malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency.

It belongs to the rare diseases. It is a recessive disorder that is accompanied by hyperphenylalaninemia. Commonly reported symptoms are initial truncal hypotonia, subsequent appendicular hypertonia, bradykinesia, cogwheel rigidity, generalized dystonia, and marked diurnal fluctuation. Other reported clinical features include difficulty in swallowing, oculogyric crises, somnolence, irritability, hyperthermia, and seizures. Chorea, athetosis, hypersalivation, rash with eczema, and sudden death have also been reported. Patients with mild phenotypes may deteriorate if given folate antagonists such as methotrexate, which can interfere with a salvage pathway through which dihydrobiopterin is converted into tetrahydrobiopterin via dihydrofolate reductase. Treatment options include substitution with neurotransmitter precursors (levodopa, 5-hydroxytryptophan), monoamine oxidase inhibitors, and tetrahydrobiopterin. Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype/phenotype correlation and outcome of these diseases their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD).

ADT tachyphylaxis specifically occurs in depressed patients using SSRIs and MAOIs. Currently, SSRIs are the preferred treatment for depression among clinicians, as MAOIs require the patient to avoid certain foods and other medications due to the potential for interactions capable of inducing dangerous side effects. Provided is a list of medications known to be subject to Poop-out.

Following a declination or total extinction in response to a previously therapeutic dose of an antidepressant, the issue is clinically addressed as stemming from tolerance development. Several strategies are available, such as exploring drug options from a different drug class used to treat depression. The patient can also choose to switch to another SSRI (or MAOI, if applicable) while maintaining proportionate dose. If tolerance develops in a drug from the same class, the clinician may recommend a regular cycle consisting of all effective treatments within the SSRI or MAOI classes, in order to minimize transitional side effects while maximizing therapeutic efficacy.

Other options include increasing dose of the same medication, or supplementation with another antidepressant. Dual reuptake inhibitors, also known as tricyclic antidepressants have been shown to have lower rates of tachyphylaxis.

CML accounts for 8% of all leukaemias in the UK, and around 680 people were diagnosed with the disease in 2011.

Painful red swelling of the hands and feet in a patient receiving chemotherapy is usually enough to make the diagnosis. The problem can also arise in patients after bone marrow transplants, as the clinical and histologic features of PPE can be similar to cutaneous manifestations of acute (first 3 weeks) graft-versus-host disease. It is important to differentiate PPE, which is benign, from the more dangerous graft-versus-host disease. As time progresses, patients with graft-versus-host disease progress to have other body parts affected, while PPE is limited to hands and feet. Serial biopsies every 3 to 5 days can also be helpful in differentiating the two disorders (Crider et al., 1986).

The cooling of hands and feet during chemotherapy may help prevent PPE (Baack and Burgdorf, 1991; Zimmerman et al., 1995). Support for this and a variety of other approaches to treat or prevent acral erythema comes from small clinical studies, although none has been proven in a randomised controlled clinical trial of sufficient size.

The first red flag that indicates M2 acute myeloblastic leukemia with maturation is the skewed ratio of white blood cells to red blood cells. Leukemia is initially diagnosed by a peripheral blood smear, a procedure used to check for cell count and cell shapes. Then a bone marrow aspiration and biopsy would be conducted to collect and view the bone, bone marrow, and blood under a microscope. Cytogenetic assays, such as fluorescence in situ hybridization (FISH) would help evaluate the structure and function of the cell’s chromosomes.

The criteria for an acute myeloid leukemia case to fall under the M2 subtype is the following: 20%+ nonerythroid cells in peripheral blood or bone marrow are myeloblasts; monocytic precursors are < 20% in bone marrow and granulocytes are 10%+ of cells (Mihova, 2013).

Before the advent of tyrosine kinase inhibitors, the median survival time for CML patients had been about 3–5 years from time of diagnosis.

With the use of tyrosine kinase inhibitors, survival rates have improved dramatically. A 2006 followup of 553 patients using imatinib (Gleevec) found an overall survival rate of 89% after five years.

A 2011 followup of 832 patients using imatinib who achieved a stable cytogenetic response found an overall survival rate of 95.2% after 8 years, which is similar to the rate in the general population. Fewer than 1% of patients died because of leukemia progression.

Generally, acute myeloid leukemia is treated using chemotherapy consisting of an induction phase and consolidation phase (Dohner et al., 2009). Patients may also consider hematopoietic stem cell transplantation as a second mode of tackling the cancer. The most novel research is being done in tyrosine kinase inhibitors; however M2 acute myeloid leukemia treatment research involves molecules that inhibit the fusion oncoprotein AML1-ETO. Therefore, in terms of M2 subtype acute myeloid leukemia, the most prominent target is the abnormal AML1-ETO fusion protein. Similarly, chronic myeloid leukemia (CML) is comparable to acute myeloid leukemia M2 because it also forms a fusion oncoprotein – BCR-Abl. The developed tyrosine kinase inhibitor, imatinib mesylate, has had a tremendous effect on stopping cancer progression in the majority of chronic myeloid leukemia patients. BCR-Abl is constitutively active due chromosome translocation; therefore it over-phosphorylates the tyrosine kinase. Imatinib mesylate works to block BCR-Abl’s activity by blocking the active kinase domain (Fava et al., 2011).

Celastrol is a compound extracted from Tripterygium wilfordii that has anti-cancer properties. It was found to inhibit cell proliferation through the down regulation of AML1-ETO fusion oncoprotein. Celastrol inhibits the fusion oncoprotein by inducing mitochondrial instability and initiating caspase activity The decrease of AML1-ETO also results in lower levels of C-KIT kinases, Akt/PKB, STAT3, and Erk1/2 – all of which are involved in cell signaling and gene transcription (Yu et al., 2016).

Histone deacetylase inhibitors such as valproic acid (VPA), vorinostat, and all-trans retinoic acid (ATRA) are effective in targeting acute myeloid leukemia with the AML1-ETO fusion protein. The HDAC inhibitors are known to induce apoptosis through accumulation of DNA damage, inhibition of DNA repair, and activation of caspases. These inhibitors are extra sensitive to the fusion proteins. Vorinostat has been proven to cause a greater accumulation of DNA damage in fusion protein expressing cells and is directly correlated with the reduction of DNA repair enzymes (Garcia et al., 2008). Romidepsin, a drug in phase two clinical trials, has demonstrated higher efficacy in patients with AML1-ETO fusion protein leukemia (Odenike et al., 2008). Although many clinical evaluations have proven HDAC inhibitors have a promising effect on M2 subtype acute myeloid leukemia, it has not been approved as an official treatment.

In t(6;9) acute myeloid leukemia, FLT3-ITD and the DEK-NUP214 protein are potential targets for treatment. Sorafenib is a kinase inhibitor used as a treatment for kidney and liver cancer. The kinase inhibitor blocks serine-threonine kinase RAF-1 as well as FLT-ITD (Kindler, 2010). The drug has been proven to be effective in reducing FLT3-ITD overexpression (Metzelder et al., 2009). In patients with DEK-NUP214, it was found that the fusion oncoprotein caused an upregulation of mTORC1 (Sanden et al., 2013). Thus, a mTORC inhibitor could be a potential treatment.

Symptoms can last for more than 4 weeks and typically resolve within a day of restoring the medication.

The diagnosis can usually be made on a combination of clinical, family history and biopsy criteria.

Antidepressants, including SSRIs, can cross the placenta and have the potential to affect the fetus and newborns, presenting a dilemma whether pregnant women should take antidepressants at all, and if they do, whether tapering them near the end of pregnancy could have a protective effect for the newborn.

Postnatal adaptation syndrome (PNAS) (originally called “neonatal behavioral syndrome”, “poor neonatal adaptation syndrome”, or "neonatal withdrawal syndrome") was first noticed in 1973 in newborns of mothers taking antidepressants; symptoms in the infant include irritability, rapid breathing, hypothermia, and blood sugar problems. The symptoms usually develop from birth to days after delivery and usually resolve within days or weeks of delivery.

Tissue biopsy is the diagnostic modality of choice. Due to a high incidence of lymph node involvement, a sentinel lymph node biopsy is often performed. A common characteristic of epithelioid sarcoma (observed in 80% of all cases) is the loss of function of the SMARCB1 gene (also termed BAF47, INI1, or hSNF5). Immunohistochemical staining of INI1 is available and can be used for the diagnosis of epithelioid sarcoma. MRI is the diagnostic modality of choice for imaging prior to biopsy and pathologic diagnosis, with the primary role being the determination of anatomic boundaries.

Most patients with "ETV6-ACSL6"-related disease present with findings similar to eosinophilia, hypereosinophila, or chronic eosinophilic leukemia; at least 4 cases presented with eosinophilia plus findings of the red blood cell neoplasm, polycythemia vera; three cases resembled acute myelogenous leukemia; and one case presented with findings of a combined Myelodysplastic syndrome/myeloproliferative neoplasm. Best treatments for "ETV6-ACSL6"-related disease are unclear. Patients with the polycythemia vera form of the disease have been treated by reducing the circulating red blood cell load by phlebotomy or suppressing red blood cell formation using hydroxyurea. Individual case studies report that "ETV6-ACSL6"-associated disease is insensitive to tyrosine kinase inhibitors. Best treatment currently available, therefore, may involve chemotherapy and bone marrow transplantion.

To be helpful, kidney biopsies need to be taken before the disease is too advanced. Changes on conventional (light) microscopy are not characteristic, and the possibility of other diagnoses, particularly focal segmental glomerulosclerosis (FSGS), may be raised. Electron microscopy shows a characteristic sequence of changes from thinning of the glomerular basement membrane (GBM), developing into areas of thinning and thickening, and finally into a complex appearance with apparent splitting, often described as a 'basketweave' appearance. Early or very localised changes on this spectrum are not diagnostic, but the later changes are considered diagnostic.

Immunohistochemistry or immunofluorescence studies to identify the COL3-4-5 proteins in GBM can be helpful. However, these studies may be normal in some patients with Alport syndrome, especially milder variants.

Skin contains type IV collagen in a '556' network. Skin biopsies have been used to show absence of the "COL4A5" gene product, but these techniques are not straightforward, only apply to patients with severe "COL4A5" mutations, and are not widely available. Genetic testing is now a better alternative if kidney biopsy is not possible.

The staging for epithelioid sarcoma takes into account size and location of the primary tumor, lymph node involvement, presence and location of metastasis, and histologic grade (a measure of disease aggressiveness)

Patients with "ETV6-ABL1" fusion gene-positive disease present with various hematological disorders. Children present predominantly with hematological findings similar to acute lymphocytic leukemia and less commonly with findings of acute myelogenous leukemia or chronic variants of these two leukemias. Adults are more likely to present with findings similar to acute myelogenous leukemia or myeloproliferative neoplasms. In a study of 44 patients with this fusion gene, eosinophilia was found in all patients with myelogenous and myeloproliferative diseases but only 4 of 13 with acute lymphocytic leukemia presentations. The prognosis was very poor in adults with acute leukemia forms of the disease; ~80% of these patients suffered fatal disease progression or relapse. Five patients with the myeloproliferative form of the disease responded to the tyrosine kinase inhibitor imatinib or sequential treatment with imatinib followed by recurrence and treatment with a second generation tyrosine kinase inhibitor nilotinib; dasatinib is also a recommended second generation tyrosine kinase inhibitor for treating the disease. Follow-up of these patients is too short to determine the overall length of time to relapse and the efficacy of single or serial tyrosine kinase inhibitor treatments. Patients with the blast cell phase of this disease have very poor responses to tyrosine kinase inhibitors and a median survival of ~1 year. Thus, tyrosine kinase inhibitors, including second-generation inhibitors, in the treatment of "ETV6-ABL1"-positive hematological malignancies have shown varying responses; it is suggested that further investigations into the clinical efficacy of these drugs in "ETV6-ABL1"-induced clonal hypereosinophilia is warranted.

Primary myelofibrosis (PMF) is associated with the "JAK2V617F" mutation in up to 50% of cases, the "JAK2" exon 12 mutations in 1-2% of cases, and the MPL (thrombopoietin receptor) mutation in up to 5% of cases:

- Prefibrotic/cellular phase - increased, small and atypical megakaryocytes which cluster, reticulin fibrosis, later trichrome (collagenous) fibrosis, and increased myeloid precursors

- Fibrotic phase - collagenous fibrosis with lack of marrow elements

Depending on the nature of the myeloproliferative neoplasm, diagnostic tests may include red cell mass determination (for polycythemia), bone marrow aspirate and trephine biopsy, arterial oxygen saturation and carboxyhaemoglobin level, neutrophil alkaline phosphatase level, vitamin B (or B binding capacity), serum urate or direct sequencing of the patient's DNA.

According to the WHO Classification of Hematopoietic and Lymphoid Neoplasms 2008 myeloproliferative neoplasms are divided into categories by diagnostic characteristics as follows:

Drug-induced angioedema is a known complication of the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II antagonists (ARBs), and Angiotensin-Neprilysin Inhibitor LCZ969. The angioedema appears to be dose dependent as it may resolve with decreased dose.

Some common ACE Inhibitors are:

- Benazepril (Lotensin)

- Captopril (Capoten)

- Enalapril (Vasotec)

- Lisinopril (Prinivil, Zestril)

- Ramipril (Altace)

Some common ARBs are:

- Candesartan (Atacand)

- Losartan (Cozaar)

- Olmesartan (Benicar)

- Valsartan (Diovan)

Angioedema presents itself as an abrupt onset of non-pitting, non-itchy swelling that involves the mucosal layers. Some common locations of angioedema are the face, particularly the lips and around the eyes, hands and feet, and genitalia. A rare, yet serious complication is one inside the abdomen, the symptom usually being severe stomach upset, which is much less obvious than the other locations.

The chance of drug-induced angioedema is extremely uncommon, however, as studies show incidence of less than 1%. The reason this adverse effect may occur is due to the build-up of bradykinin, a vasodilator. This causes blood vessels to dilate and allow for fluid buildup in the mucosal surfaces.

As one route to reducing TAMs CSF1R inhibitors have been developed as a possible cancer therapy and many are in early clinical trials. CSF1R inhibitors in clinical trials include : Pexidartinib, PLX7486, ARRY-382, JNJ-40346527, BLZ945, Emactuzumab, AMG820, IMC-CS4. (MCS110 is a CSF1 inhibitor)

Another CSF1R inhibitor that targets/depletes TAMs is Cabiralizumab (cabira; FPA-008) which is a monoclonal antibody and is in early clinical trials for metastatic pancreatic cancer.

Reversion of lipodystrophy does not occur after withdrawal of protease inhibitors.

GHRH analogs such as tesamorelin can be used to treat HIV-associated lipodystrophy.