Salvatore Cocuzza

Mucosal Leishmaniasis: An Underestimated Presentation of a Neglected Disease

We present a review of current knowledge about mucosal leishmaniasis (ML). Although involvement of mucous membranes is classically admitted in New World leishmaniasis, particularly occurring in infection by Leishmania (L.) braziliensis species complex, ML is also a possible presentation of Old World leishmaniasis, in either L. donovani or L. major species complex infections. Thus, ML has to be considered not only as a Latin American disease but as an Old and New World disease. We describe ML epidemiology, pathogenesis, clinics, diagnosis, and therapy. Considering both its highly disfiguring lesions and its possible lethal outcome, ML should not be underestimated by physicians. Moreover, leishmaniasis is expected to increase its burden in many countries as sandfly vector distribution is widespreading towards non-endemic areas. Finally, the lack of clear understanding of ML pathogenesis and the absence of effective human vaccines strongly claim for more research.

Childhood neurofibromatosis type 2 (NF2) and related disorders: from bench to bedside and biologically targeted therapies

SUMMARY Neurofibromatosis type 2 [NF2; MIM # 101000] is an autosomal dominant disorder characterised by the occurrence of vestibular schwannomas (VSs), schwannomas of other cranial, spinal and cutaneous nerves, cranial and spinal meningiomas and/or other central nervous system (CNS) tumours (e.g., ependymomas, astrocytomas). Additional features include early onset cataracts, optic nerve sheath meningiomas, retinal hamartomas, dermal schwannomas (i.e., NF2-plaques), and (few) café-au-lait spots. Clinically, NF2 children fall into two main groups: (1) congenital NF2 - with bilateral VSs detected as early as the first days to months of life, which can be stable/asymptomatic for one-two decades and suddenly progress; and (2) severe pre-pubertal (Wishart type) NF2- with multiple (and rapidly progressive) CNS tumours other-than-VS, which usually present first, years before VSs [vs. the classical adult (Gardner type) NF2, with bilateral VSs presenting in young adulthood, sometimes as the only disease feature]. Some individuals can develop unilateral VS associated with ipsilateral meningiomas or multiple schwannomas localised to one part of the peripheral nervous system [i.e., mosaic NF2] or multiple non-VS, non-intradermal cranial, spinal and peripheral schwannomas (histologically proven) [schwannomatosis]. NF2 is caused by mutations in the NF2 gene at chromosome 22q12.1, which encodes for a protein called merlin or schwannomin, most similar to the exrin-readixin-moesin (ERM) proteins; mosaicNF2 is due to mosaic phenomena for the NF2 gene, whilst schwannomatosis is caused by coupled germ-line and mosaic mutations either in the SMARCB1 gene [SWNTS1; MIM # 162091] or the LZTR1 gene [SWNTS2; MIM # 615670] both falling within the 22q region and the NF2 gene. Data driven from in vitro and animal studies on the merlin pathway [e.g., post-translational and upstream/downstream regulation] allowed biologically targeted treatment strategies [e.g., Lapatinib, Erlotinib, Bevacizumab] aimed to multiple tumour shrinkage and/or regression and tumour arrest of progression with functional improvement.

Epilepsy and innate immune system: A possible immunogenic predisposition and related therapeutic implications

Recent experimental studies and pathological analyses of patient brain tissue samples with refractory epilepsy suggest that inflammatory processes and neuroinflammation plays a key-role in the etiopathology of epilepsy and convulsive disorders. These inflammatory processes lead to the secretion of pro-inflammatory cytokines responsible for blood-brain-barrier disruption and involvement of resident immune cells in the inflammation pathway, occurring within the Central Nervous System (CNS). These elements are produced through activation of Toll-Like Receptors (TLRs) by exogenous and endogenous ligands thereby increasing expression of cytokines and co-stimulatory molecules through the activation of TLRs 2, 3, 4, and 9 as reported in murine studies.It has been demonstrated that IL-1β intracellular signaling and cascade is able to alter the neuronal excitability without cell loss. The activation of the IL-1β/ IL-1β R axis is strictly linked to the secretion of the intracellular protein MyD88, which interacts with other cell surface receptors, such as TLR4 during pathogenic recognition. Furthermore, TLR-signaling pathways are able to recognize molecules released from damaged tissues, such as damage-associated molecular patterns/proteins (DAMPs). Among these molecules, High-mobility group box-1 (HMGB1) is a component of chromatin that is passively released from necrotic cells and actively released by cells that are subject to profound stress. Moreover, recent studies have described models of epilepsy induced by the administration of bicuculline and kainic acid that highlight the nature of HMGB1-TLR4 interactions, their intracellular signaling pathway as well as their role in ictiogenesis and epileptic recurrence.The aim of our review is to focus on different branches of innate immunity and their role in epilepsy, emphasizing the role of immune related molecules in epileptogenesis and highlighting the research implications for novel therapeutic strategies.

Audiological range in Turner's syndrome.

Turners syndrome is generally characterised by bilateral gonadal disgenesis, short stature and inadequate sexual development secondary to anomalous karyotype. The purely otorhinolaryngoiatric pathology considerably influences the symptomatological features in Turners subject and this is based on possible morphologically structured anomalies in the external, middle and inner ear, but also on the oral cavity and pharynx. From this there is evidence of otological emergence on a phlogistic infectious basis with remarkable long-term repercussion on the hearing process. Otofunctional evaluation in 21 Turners syndrome patients shows predominance of conductive hearing loss (42.8%), proven through evidence of otitis media (33.3%) and chronic otitis media (9.5%). This, therefore, demands an attentive audiologic monitoring related to the possible development of chronic forms or cholesteatoma and the possible rehabilitative-prothesis procedure.

Early history of neurofibromatosis type 2 and related forms: earliest descriptions of acoustic neuromas, medical curiosities, misconceptions, landmarks and the pioneers behind the eponyms

As in many diseases, exactly which was the first case report of “neurofibromatosis” and who truly deserves the eponymous for credit have been a matter of debate [6, 42, 66]. Certainly, in the past centuries, several renowned “patients” taken from fiction or reality have been labelled as having this condition and, among all, Joseph Merrick also known as the “elephant man” [11, 41, 77, 87] and Quasimodo the “hunchback” of “Notre Dame de Paris” by Victor Hugo [12, 76] are two infamous examples who played an important role in the distorted popular misconception of the disease. The history of neurofibromatosis (in this case neurofibromatosis type 1—NF1), in fact, can be traced to ancient times, if descriptions of grotesque or distorted persons are considered [1, 6, 37, 42, 51, 54, 100]. Similarly, reports of early examples of neurofibromatosis type 2 (NF2) or schwannomatosis sufferers can be traced in descriptions, illustrations or portraits dated as far back as the eighteenth century [1, 6, 42]. In this article, we will review these developments focusing on the most acknowledged descriptions of patients with NF2 in history.

Blood pressure and occupational exposure to noise and lead (Pb) A cross-sectional study

Several studies have explored the hypothesis that low blood lead (PbB) and high noise levels may be associated with an increased risk of hypertension. To assess the possible relationship between occupational exposure to lead (Pb) and noise and elevated blood pressure, we studied 105 workers (age: 41.27 ± 6.25 years and length of employment: 4.12 ± 5.33 years) employed in a Pb battery recycling plant by measuring A-weighted equivalent sound level, PbB, δ-aminolevulinic acid dehydratase (ALAD) activity and zinc protoporphyrin (ZPP) levels and systolic and diastolic blood pressure (SBP and DBP). Results showed that occupational exposure to higher ambient Pb and noise levels was related to slightly increased SBP and DBP. PbB values correlated significantly with SBP and DBP, whereas noise levels correlated neither with SBP nor with DBP. Furthermore, workers exposed to higher ambient Pb had higher PbB and ZPP and showed more decreased ALAD activity. Blood pressure does not correlate with noise exposure but only with PbB concentration.

Pediatric autoimmune neuropsychiatric disorder associated with group a streptococcal infection: the role of surgical treatment.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) is a well-defined syndrome in which tics (motor and/or vocal) and/or obsessive compulsive disorders (OCD) consistently exacerbate in temporal correlation to a Group A beta-haemolytic streptococcal infection. In children with PANDAS, there is speculation about whether tonsillectomy or adenotonsillectomy might improve the neuropsychiatric course. Our objective was to examine whether such surgery impacted remission or, in patients without remission, modified clinical course of the disease, streptococcal antibody titers, neuronal antibodies or clinical severity of Obsessive-Compulsive Disorder (OCD) and/or tics. Study participants (n = 120) with positive PANDAS criteria were recruited, examined, and divided into surgical or non-surgery groups. The surgical group consisted of children with tonsillectomy or adenotonsillectomy (n=56). The remaining children were categorized as non-surgery (n=64). Clinical follow-up was made every 2 months for more than 2 years. Surgery did not affect symptomatology progression, streptococcal and neuronal antibodies, or the clinical severity of neuropsychiatric symptoms in these children. In conclusion, in our series clinical progression, antibody production, and neuropsychiatric symptom severity did not differ on the basis of surgical status. We cannot uphold surgical management as likely to impact positive remission rates, course of OCD/tics, or antibody concentrations in children with PANDAS.

The usefulness of immunotherapy in pediatric neurodegenerative disorders: A systematic review of literature data

Immunotherapeutic strategies to treat neurodegenerative disorders have inspired the scientific community. The aim of our review is to address the translational aspects of neuroimmunology to describe the efficacy of immunotherapy in the treatment of pediatric neurodegenerative disorders. In the studies we analyzed IVIG were found to be efficient in the treatment of post-streptococcal neurodegenerative disorders, even if in PANDAS, plasma-exchange (PE) showed a higher efficiency. IVIG were also successfully used in ADEM and Guillan-Barré syndrome. In Sydenham Chorea the use of methylprednisolone was found in most cases as efficient as IVIG, while in Tourettes Syndrome, Colecoxib was successfully used in one patient. Pediatric Multiple Sclerosis seems to respond better to immunosuppressant agents (Mitoxantrone, Cyclophosphamide, Natalizumab), as well as Neuromyelitis optica (Rituximab, Mycofenolate). The importance of this review relies in the attempt to draw standardized guidelines for immunotherapy in pediatric neurodegeneratve disorders

Isolated laryngeal leishmaniasis in immunocompetent patients: an underdiagnosed disease.

We describe a case of isolated primary laryngeal leishmaniasis in an immunocompetent Italian patient with a previous medical history negative for visceral or cutaneous leishmaniasis, presenting with hoarseness. We also summarize the epidemiological, clinical, and diagnostic features and the therapeutic management of other cases of laryngeal leishmaniasis in immunocompetent subjects, described in the literature. Considering the insidious and nonspecific clinical presentation, the increasing number of different forms of mild or underestimated immunosuppressive conditions, and the number of people travelling in endemic zones, along with the ability of Leishmania amastigotes to survive for a long period in the body, we believe it is important for pathologists and clinicians to be aware of this unusual form of leishmaniasis in order to avoid delayed recognition and treatment. The rarity of the presentation and the lack of guidelines on mucosal leishmaniasis may contribute to the potential undiagnosed cases or delayed diagnosis, the possible relapses, as well as the correct pharmacological and/or surgical therapeutic approach.

Incidence of Mediterranean spotted fever in Sicilian children: a clinical-epidemiological observational retrospective study from 1987 to 2010.

BACKGROUND Zoonoses are human infectious diseases caused by pathogens that primarily infect animals. Mediterranean Spotted Fever (MSF) represents one such example, affecting the Mediterranean region, in which household animals can be immune-carriers of infected ticks. MATERIALS AND METHODS We retrospectively analysed the incidence and the clinical and laboratory features of MSF caused by R.Conorii in children admitted to the Paediatric Operative Unit from 1987 to 2010, for persistent fever and generalised macular-popular erythematous lesions. Clinical, immunological and serological parameters of 55 cases of Rickettsia infections observed in children between 2 and 11 years of age were collected. RESULTS We found an increasing incidence of MSF in childhood from 1987 to 2010. Diagnosis of MSF at the moment of hospital admission was done in 16 patients (29.09%). The presence of the typical Tache noire was observed in 16 cases out of 55 patients (29.09% of cases). We noticed a different representation of R. conorii antigens in serological testing over the time period of the study, corresponding to overall higher incidence rates for infection in the latter years. We also observed a higher incidence of infection in those years in which all four antigens were found positive at serum testing with respect to those years in which only two of the four antigens were observed (1987-1990: 0-16%; 2007-2010: 0.46%; P<0.005). CONCLUSIONS These changes in R. conorii antigenicity may be the cause of higher pathogenicity in this parasite, perhaps linked to increased immigration along with consequent changes in the epidemiology of infectious diseases in host countries.